Manufacture of 4-((1r,3s)-6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine and 1-((1r,3s)-6-chloro-3-phenyl-indan-1-yl)-3,3-dimethyl-piperazine

The present invention relates to a process for the manufacture of 4-((1R,3S)-6-Chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine or a pharmaceutically acceptable salt thereof and a process for the manufacture of 1-((1R,3S)-6-Chloro-3-phenyl-indan-1-yl)-3,3-dimethyl-piperazine or a pharmaceutically acceptable salt thereof.

TARGETED NITROXIDE AGENTS

Provided herein are compositions and related methods useful for free radical scavenging, with particular selectivity for mitochondria. The compounds comprise a nitroxide-containing group attached to a mitochondria-targeting group. The compounds can be cross-linked into dimers without loss of activity. Also provided herein are methods, for preventing, mitigating and treating damage caused by radiation. The method comprises delivering a compound, as described herein, to a patient in an amount and dosage regimen effective to prevent, mitigate or treat damage caused by radiation. 45-. (canceled)6. The compound of claim 1 , in which R is Ac claim 1 , Boc claim 1 , Cbz claim 1 , or —P(O)-Ph.7. The compound of claim 1 , in which R claim 1 , R claim 1 , Rand Rare independently chosen from hydrogen claim 1 , methyl claim 1 , ethyl claim 1 , propyl claim 1 , 2-propyl claim 1 , butyl claim 1 , t-butyl claim 1 , pentyl claim 1 , hexyl claim 1 , benzyl claim 1 , hydroxybenzyl claim 1 , phenyl and hydroxyphenyl.8. The compound of claim 1 , wherein when X is —CH═CR— claim 1 , Ris hydrogen claim 1 , methyl or ethyl.912-. (canceled)13. The compound of in which R1 claim 1 , R2 and R3 independently are methyl claim 1 , ethyl claim 1 , propyl claim 1 , 2-propyl claim 1 , butyl claim 1 , t-butyl claim 1 , pentyl claim 1 , hexyl claim 1 , benzyl claim 1 , hydroxybenzyl claim 1 , phenyl and hydroxyphenyl.1421-. (canceled)27. A method of making a targeted antioxidant compound claim 1 , comprising:{'sub': 1', '1', '1', '6', '6', '5, 'a. reacting an aldehyde of structure R—C(O)— with (R)-2-methylpropane-2-sulfinamide to form an imine, in which Ris C-Cstraight or branched-chain alkyl, optionally including a phenyl (CH) group, that optionally is methyl-, hydroxyl- or fluoro-substituted;'}{'sub': 2', '2', '2, 'b. reacting a terminal alkyne-1-ol (HCC—R—CH—OH), in which Ris not present or is branched or straight-chained alkylene, with a tert-butyl)diphenylsilane salt to produce an alkyne;'}c. ...

PIPERIDINE DERIVATIVES

The present invention relates to a compound of formula I 2. A compound of claim 1 , wherein Ris lower alkyl.3. A compound of claim 2 , wherein the phenyl group for Ar is substituted by at least two CFgroups.4. A compound of claim 3 , selected from the group consisting ofrac-2-fluoro-N-(1-methyl-3-phenyl-piperidin-3-yl)-4,6-bis-trifluoromethyl-benzamide;rac-2-methoxy-N-(1-methyl-3-phenyl-piperidin-3-yl)-4,6-bis-trifluoromethyl-benzamide;rac-2-ethyl-N-(1-methyl-3-phenyl-piperidin-3-yl)-4,6-bis-trifluoromethyl-benzamide;rac-N-[3-(4-fluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-4,6-bis-trifluoromethyl-benzamide; and2-methoxy-N—((R)-1-methyl-3-phenyl-piperidin-3-yl)-4,6-bis-trifluoromethyl-benzamide.5. A compound of claim 1 , wherein the phenyl group for Ar is substituted by at least one CFgroup.6. A compound of claim 5 , selected from the group consisting ofrac-2-ethyl-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;rac-2-bromo-6-methoxy-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;rac-N-(1,2-dimethyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;rac-2-cyclopropyl-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;rac-2-methoxy-N-(1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;rac-N-(1-methyl-3-phenyl-piperidin-3-yl)-2-methylsulfanyl-4-trifluoromethyl-benzamide;rac-N-[3-(4-fluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;rac-N-[3-(4-chloro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;2-methoxy-N-((S)-1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;2-methoxy-N—((R)-1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide; andrac-2-difluoromethoxy-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide.7. A compound of claim 5 , selected from the group consisting ofrac-N-[3-(3-chloro-phenyl)-1-methyl- ...

CARBOXAMIDE BIOISOSTERES OF OPIATES

A compound of formula I is disclosed. 111-. (canceled)13. A method according to wherein said disease or condition is chosen from the group consisting of pain claim 12 , pruritis claim 12 , diarrhea claim 12 , irritable bowel syndrome claim 12 , gastrointestinal motility disorder claim 12 , obesity claim 12 , respiratory depression claim 12 , convulsions claim 12 , coughing claim 12 , hyperalgesia claim 12 , inflammation claim 12 , osteoarthritis and drug addiction.14. A method according to wherein said drug addiction is selected from heroin claim 13 , cocaine claim 13 , nicotine claim 13 , amphetamine and alcohol addiction.15. A method according to claim 13 , wherein the condition is pain and the composition further comprises an effective amount of an opioid.16. A method according to claim 13 , wherein the condition is osteoarthritis and the composition further comprises an effective amount of an opioid.1732-. (canceled)33. A method according to claim 12 , wherein Rand Rare hydrogen.34. A method according to claim 12 , wherein Ris —OH claim 12 , —CHO claim 12 , —CONH claim 12 , —CON(H)CHCONH claim 12 , —CON(H)CHCHCONH claim 12 , —CON(H)CHCOOH claim 12 , or —CON(H)CHCHCOOH; or Rand Rtogether with the atoms to which they are attached forms a —OCHO— fused ring.35. A method according to claim 12 , wherein Ris H.39. A method according to wherein Ris in the para position relative to B and Ris hydrogen or methyl; or Rand Rtogether with the atoms to which they are attached claim 38 , and a fragment selected from —OCHO— or —OCHCHO— claim 38 , form a ring.44. A method according to wherein Ris in the para position relative to B and Ris hydrogen.45. A method according to claim 12 , wherein Aris phenyl and one of Ror Ris in the para position relative to B. This application is a divisional application of U.S. patent application Ser. No. 13/069,104, filed Mar. 22, 2011, now allowed. U.S. patent application Ser. No. 13/069,104 claims priority of U.S. provisional applications 61/316 ...

4-HYDROXYBENZOMORPHANS

4-Hydroxybenzomorphans containing carboxamide or thiocarboxamide at the 3-position are useful as analgesics, anti-diarrheal agents, anticonvulsants, antitussives and anti-addiction medications. A compound of formula This application is a continuation application of U.S. application Ser. No. 11/760,039, filed Jun. 8, 2007, which was a divisional application of U.S. application Ser. No. 11/266,651, filed Nov. 3, 2005, and issued as U.S. Pat. No. 7,262,298 on Aug. 28, 2007. U.S. application Ser. No. 11/266,651 claims priority from U.S. Provisional Application 60/625,348 filed Nov. 5, 2004. The entire disclosures of each of the prior applications are hereby incorporated herein by reference.The invention relates to 4-hydroxybenzomorphans substituted at the 3-position with carboxamide or thiocarboxamide. The compounds are useful as analgesics, anti-diarrheal agents, anticonvulsants, antitussives, anti-cocaine, and anti-addiction medications.Opiates have been the subject of intense research since the isolation of morphine in 1805, and thousands of compounds having opiate or opiate-like activity have been identified. Many opioid receptor-interactive compounds including those used for producing analgesia (e.g., morphine) and those used for treating drug addiction (e.g., naltrexone and cyclazocine) have been employed in human therapy. Almost all therapeutically useful opioids in the benzazocine and morphinane classes have a phenolic hydroxyl group (OH) at a position which is numbered “8” in the numbering system used for 2,6-methano-3-benzazocines [e.g., cyclazocine and EKC (ethylketocyclazocine)] and which is numbered “3” in the numbering system used for morphinanes (e.g., morphine).Although the compounds of the present invention do not possess the furan ring of the morphinans, the morphinan numbering system will be used:2,6-Methano-3-benzazocines are also known as benzomorphans, and this terminology will be used interchangeably herein.Until the publications of Wentland et al ...

Modulators of Muscarinic Receptors

The present invention relates to modulators of muscarinic receptors. The present invention also provides compositions comprising such modulators, and methods therewith for treating muscarinic receptor mediated diseases. 171-. (canceled)73. The method according to claim 72 , wherein G is an optionally substituted bicyclic group of formula (III) in which ring B is absent.74. The method according to claim 73 , wherein Xis —(CH)—.75. The method according to claim 74 , wherein G is optionally substituted bicyclo[2.2.1]heptyl claim 74 , bicyclo[3.2.1]octyl claim 74 , bicyclo[3.3.1]nonyl claim 74 , bicyclo[2.2.2]octyl claim 74 , or bicyclo[2.2.1]heptanyl.76. The method according to claim 75 , wherein G is substituted with 1 to 2 substituents independently selected from Q claim 75 , and —C(O)—X-aliphatic claim 75 , where Xis absent claim 75 , —O— claim 75 , —NH— claim 75 , or —NQ- claim 75 , and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q.77. The method according to claim 73 , wherein Xis —N(Q)— or —N(C(O)—X-aliphatic) claim 73 , where Xis absent claim 73 , —O— claim 73 , —NH— claim 73 , or —NQ- claim 73 , and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q.78. The method according to claim 77 , wherein G is an optionally substituted tropane.79. The method according to claim 78 , wherein the tropane is substituted with Q claim 78 , or —C(O)—X-aliphatic claim 78 , where Xis absent claim 78 , —O— claim 78 , —NH— claim 78 , or —NQ- claim 78 , and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q.80. The method according to claim 78 , wherein the tropane is substituted at the tropane ring nitrogen atom with alkoxycarbonyl claim 78 , alkoxyalkoxycarbonyl claim 78 , heterocycloalkoxy carbonyl claim 78 , cycloalkoxycarbonyl claim 78 , alkoxyaryloxycarbonyl claim 78 , alkylaminocarbonyl claim 78 , haloalkoxy carbonyl claim 78 , ...

PERIPHERAL OPIOID RECEPTOR ANTAGONISTS AND USES THEREOF

The present invention provides a compound of formula I: 118-. (canceled)20. The composition of claim 19 , wherein X is selected from the group consisting of the anion of a suitable BrØnsted acid claim 19 , a hydrogen halide claim 19 , a carboxylic acid claim 19 , a sulfonic acid claim 19 , a sulfuric acid claim 19 , a phosphoric acid claim 19 , chloride claim 19 , bromide claim 19 , iodide claim 19 , fluoride claim 19 , bisulfate claim 19 , tartrate claim 19 , nitrate claim 19 , citrate claim 19 , bitartrate claim 19 , carbonate claim 19 , phosphate claim 19 , malate claim 19 , maleate claim 19 , fumarate sulfonate claim 19 , methylsulfonate claim 19 , formate claim 19 , carboxylate claim 19 , sulfate claim 19 , methylsulfate and succinate.21. The composition of claim 19 , wherein Ris Caliphatic and Ris lower alkyl;{'sup': '1', 'optionally wherein Ris a (cycloalkyl)alkyl group or alkenyl group, or'}{'sup': 1', '2, 'optionally wherein Ris cyclopropyl methyl or allyl and Ris methyl.'}24. The composition of claim 23 , wherein X is selected from the group consisting of the anion of a suitable BrØnsted acid claim 23 , a hydrogen halide claim 23 , a carboxylic acid claim 23 , a sulfonic acid claim 23 , a sulfuric acid claim 23 , a phosphoric acid claim 23 , chloride claim 23 , bromide claim 23 , iodide claim 23 , fluoride claim 23 , bisulfate claim 23 , tartrate claim 23 , nitrate claim 23 , citrate claim 23 , bitartrate claim 23 , carbonate claim 23 , phosphate claim 23 , malate claim 23 , maleate claim 23 , fumarate sulfonate claim 23 , methylsulfonate claim 23 , formate claim 23 , carboxylate claim 23 , sulfate claim 23 , methylsulfate and succinate.25. The composition of claim 23 , wherein Ris Caliphatic and Ris lower alkyl;{'sup': '1', 'optionally wherein Ris a (cycloalkyl)alkyl group or alkenyl group, or'}{'sup': 1', '2, 'optionally wherein Ris cyclopropyl methyl or allyl and Ris methyl.'}28. The compound of claim 27 , wherein X is selected from the group consisting ...

TETRAHYDROISOQUINOLINE DERIVATIVE

To provide an excellent agent for preventing or treating dementia and schizophrenia based on serotonin 5-HTreceptor regulating action, it was found that a tetrahydroisoquinoline derivative characterized by a structure in which an acylguanidino group binds to a N atom of a tetrahydroisoquinoline ring or the like, and a cyclic group binds to an unsaturated ring has a potent 5-HTreceptor regulating action and an excellent pharmacological action based on the regulating action and also discovered that the tetrahydroisoquinoline derivative is useful as an agent for treating or preventing dementia, schizophrenia, and the like, whereby the present invention has been completed. 2. The compound according to or a pharmaceutically acceptable salt thereof claim 1 ,{'sup': 1', '1', '2', '3', '4, 'wherein Rrepresents phenyl, pyridyl, or cycloalkyl which may be respectively substituted with group(s) selected from G, Rrepresents halogen, m represent 1, n represents 1, and both Rand Rrepresent H.'}3. The compound according to or a pharmaceutically acceptable salt thereof claim 1 ,{'sup': 1', '2', '3', '4, 'wherein Rrepresents phenyl which may be substituted with halogen or —O-(lower alkyl), Rrepresents H, F, Cl, or methyl, m represents 1, n represents 1, and both Rand Rrepresent H.'}4. The compound according to or a pharmaceutically acceptable salt thereof claim 1 ,{'sup': 1', '2', '3', '4, 'wherein Rrepresents pyridyl which may be substituted with halogen or —O-(lower alkyl), Rrepresents H, F, Cl, or methyl, m represents 1, n represents 1, and both Rand Rrepresent H.'}5. The compound according to or a pharmaceutically acceptable salt thereof claim 1 ,{'sup': 1', '2', '3', '4, 'wherein Rrepresents phenyl which may be substituted with halogen or —O-(lower alkyl), Rrepresents H, F, Cl, or methyl, m represents 1, n represents 1, and Rand Rform cyclopropane-1,1-diyl or cyclobutane-1,1-diyl together with the carbon atom binding thereto, as ethylene or trimethylene.'}6. A compound selected ...

CROSS-LINKED CYCLIC AMINE COMPOUNDS AND AGENTS FOR PEST CONTROL

Cyclic amine compounds represented by formula (1) 116-. (canceled)19. Cyclic amine compounds according to claim 17 , wherein Cyrepresents a pyridazyl group substituted by halogen claim 17 , nitro claim 17 , or haloalkyl.20. Agents for pest control comprising at least one of the cyclic amine compounds of . The present invention relates to novel cyclic amine compounds and agents for pest control which contain these cyclic amine compounds or the like as active ingredients.Priority is claimed on Japanese Patent Application No. 2005-294126, filed Oct. 6, 2005, Japanese Patent Application No. 2005-294127, filed Oct. 6, 2005, Japanese Patent Application No. 2005-297803, filed Oct. 12, 2005, Japanese Patent Application No. 2005-297804, filed Oct. 12, 2005, Japanese Patent Application No. 2006-016877, filed Jan. 25, 2006, and Japanese Patent Application No. 2006-182314, filed Jun. 30, 2006, the contents of which are incorporated herein by reference.Although many compounds which have insecticidal/acaricidal activities are conventionally known, there are problems such as insufficient effect thereof, limitation of use thereof because of drug resistance problems, occurrence of phytotoxicity or contamination in plant bodies, or strong toxicity against mammalians, fish, or the like.As compounds with backbones similar to those of the compounds of the present invention, compounds represented by the formula below are known.In the formula, X represents —O—, —N(R)—, —S—, or the like and Rrepresents a substituted saturated heterocyclic group or the like. As a representative of such compounds, the compound represented by the formula below is known (refer to Patent document 1).Moreover, the compounds represented by the formula below are known.In the formula, X represents —CH— or the like; Z represents a bonding or the like; Rrepresents an optionally substituted aryl or an optionally substituted heteroaryl; and Rand Rrepresent —(CH)— or the like together. However, when Rand Rrepresent —(CH ...

NOVEL MORPHINANS USEFUL AS ANALGESICS

Compounds of Formula (I) are disclosed. 2. A compound or salt of claim 1 , wherein{'sub': 1', '2', '3', '4', '5', '6', '6a', '7', '8', '9', '11, 'R, R, R, R, R, R, R, R, R, R, and Rare independently selected from'}(i) hydrogen, hydroxyl, cyano, and halogen; and{'sub': 11', '12', '2', '11', '12', '11', '12', '11', '12', '1', '6, '(ii) hydrocarbyl and heteroatom-containing hydrocarbyl, each of which (ii) is unsubstituted or substituted with one or more substituents independently chosen from hydroxyl, amino, cyano, halogen, oxo, —COOH, —CONRR, —SONRR, and —NRCOR, where Rand Rare independently hydrogen and C-Calkyl; and'}{'sub': 10', '10', '11', '12', '2', '11', '12', '11', '12', '11', '12', '1', '6, 'Ris hydrocarbyl or carbon-linked, heteroatom-containing hydrocarbyl, which Ris unsubstituted or substituted with one or more substituents independently chosen from hydroxyl, amino, cyano, halogen, oxo, —COOH, —CONRR, —SONRR, and —NRCOR, where Rand Rare independently chosen from hydrogen and C-Calkyl.'}7. A compound or salt of claim 1 , where{'sub': 1', '2', '4', '5', '6', '6a', '7', '8', '9', '11, 'R, R, R, R, R, R, R, R, R, and Rare independently selected from'}(i) hydrogen, hydroxyl, cyano, and halogen; and{'sub': 1', '8', '2', '8', '3', '7', '0', '4', '11', '12', '2', '11', '12', '11', '12', '11', '12', '1', '6, '(ii) C-Calkyl, C-Calkenyl, and (C-Ccycloalkyl)C-Calkyl, each containing zero or one or two heteroatoms independently chosen from N, O, and S, each of which (ii) is unsubstituted or substituted with one or more substituents independently chosen from hydroxyl, amino, cyano, halogen, oxo, —COOH, —CONRR, —SONRR, and —NRCOR, where Rand Rare independently chosen from hydrogen and C-Calkyl;'}{'sub': '3', 'Ris'}(i) hydroxyl, halogen, or{'sub': 1', '8', '2', '8', '3', '7', '0', '4', '11', '12', '2', '11', '12', '11', '12', '11', '12', '1', '6, '(ii) C-Calkoxy, C-Calkenyloxy, and (C-Ccycloalkyl)C-Calkoxy, each containing zero or one or two heteroatoms independently ...

LARGE SUBSTITUENT, NON-PHENOLIC OPIOIDS AND METHODS OF USE THEREOF

8-Substituted-2,6-methano-3-benzazocines of general structure This application is a divisional of allowed U.S. application Ser. No. 13/215,392, filed Aug. 23, 2011; which is a continuation of U.S. application Ser. No. 12/477,223, filed Jun. 3, 2009, and issued as 8,026,252 on Sep. 27, 2011; which is a continuation of U.S. application Ser. No. 11/459,203, filed Jul. 21, 2006, and issued as 7,557,119 on Jul. 7, 2009; and claims priority of U.S. provisional application 60/701,407, filed Jul. 21, 2005. The entire disclosures of each of the prior applications are hereby incorporated herein by reference.The following invention was made with Government support under contract number 5 R01 DA12180 awarded by U.S. Dept of Health and Human Services. The Government has certain rights in this invention.The invention relates to opioid receptor binding compounds containing carboxamides that have large substitutents on the nitrogen of the carboxamide. The compounds are useful as analgesics, anti-diarrheal agents, anticonvulsants, anti-obesity agents, antitussives, anti-cocaine, and anti-addiction medications.Opiates have been the subject of intense research since the isolation of morphine in 1805, and thousands of compounds having opiate or opiate-like activity have been identified. Many opioid receptor-interactive compounds including those used for producing analgesia (e.g., morphine) and those used for treating drug addiction (e.g., naltrexone and cyclazocine) in humans have limited utility due to poor oral bioavailability and a very rapid clearance rate from the body. This has been shown in many instances to be due to the presence of the 8-hydroxyl group (OH) of 2,6-methano-3-benzazocines, also known as benzomorphans [(e.g., cyclazocine and EKC (ethylketocyclazocine)] and the corresponding 3-OH group in morphinanes (e.g., morphine).The high polarity of these hydroxyl groups retards oral absorption of the parent molecules. Furthermore, the 8-(or 3-)OH group is prone to ...

Papaver bracteatum with modified alkaloid content

The present invention relates to genetically modified plants of the species Papaver bracteatum wherein the type or amount of one or more alkaloids produced by the plants has been modified. Specifically, the genetically modified plants have an increased expression of one or more of thebaine 6-O-demethylase, codeine O-demethylase and/or codeinone reductase relative to wild type P. bracteatum such that the genetically modified poppy plants produce an increased quantity of an alkaloid selected from codeine, oripavine and/or morphine relative to a wild type P. bracteatum . Also provided are progeny plants having the genetically modified poppy plants described above as a parent; mutant or derivative plants of the aforementioned plants; reproductive material derived from, straw produced from, straw concentrate produced from, latex derived from, or one or more isolated cells derived from, the aforementioned plants. Methods for producing an alkaloid from the aforementioned plants are also provided, together with nucleic acid and amino acid sequence variants of the 6-O-demethylase and codeine O-demethylase genes.

Patch preparation

A patch preparation containing a support and an adhesive layer formed on one surface of the support, wherein the adhesive layer contains 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine or a physiologically acceptable acid addition salt thereof, an acrylic polymer, lactic acid, sesame oil and one or more kinds of stabilizers selected from 2-mercaptobenzimidazole, 2,6-di-tert-butyl-4-methylphenol and propyl gallate. A patch preparation containing a support and an adhesive layer containing lactic acid and magnesium aluminometasilicate and formed on at least one surface of the support, which preparation is superior in both skin permeability and adhesiveness in the presence of water.

INSECTICIDAL SPIRONINDANE DERIVATIVES

An insecticidal compound of formula I 2. A compound according to claim 1 , wherein X is NH and Y is a single bond or C═O.3. A compound according to claim 1 , wherein each Ra is hydrogen and Rand Rare each independently hydrogen claim 1 , Calkyl claim 1 , Chaloalkyl claim 1 , Calkoxy or cyano.4. A compound according to claim 1 , wherein{'sup': 1', '13', '14, 'sub': 1-6', '1-6', '1-6', '3-7', '1-4', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-4', '1-4', '1-4', '1-4', '2', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '2-6', '2-6', '3-6', '5-7', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6, 'Ris hydrogen; Calkyl; Ccyanoalkyl; Chaloalkyl; Ccycloalkyl(C)alkyl; Calkoxy(C)alkyl; heteroaryl(C)alkyl wherein the heteroaryl group may be optionally substituted by halo, nitro, cyano, Calkyl, Chaloalkyl, Calkoxy, Chaloalkoxy, Calkylsulfonyl, Calkylsulfinyl, Calkylthio, Calkoxycarbonyl, Calkylcarbonylamino, or arylcarbonyl, or two adjacent positions on the heteroaryl ring may be cyclised to form a 5, 6 or 7 membered carbocyclic or heterocyclic ring, itself optionally substituted with halogen; aryl(C)alkyl wherein the aryl group may be optionally substituted by halo, nitro, cyano, Calkyl, Chaloalkyl, Calkoxy, Chaloalkoxy, Calkylsulfonyl, Calkylsulfinyl, Calkylthio, Calkoxycarbonyl, Calkylcarbonylamino, or arylcarbonyl, or two adjacent positions on the aryl ring may be cyclised to form a 5, 6 or 7 membered carbocyclic or heterocyclic ring, itself optionally substituted with halogen; Calkylcarbonylamino(C)alkyl; aryl which may be optionally substituted by halo, nitro, cyano, Calkyl, Chaloalkyl, Calkoxy, Chaloalkoxy, Calkylsulfonyl, Calkylsulfinyl, Calkylthio, Calkoxycarbonyl, Calkylcarbonylamino, or arylcarbonyl, or ...

Fused and Spirocycle Compounds and the Use Thereof

The invention relates to fused and spirocycle compounds of Formula (I), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein R, R, Q-Q, and Z are defined as set forth in the specification. The invention is also directed to the use of compounds of Formula (I) to treat, prevent or ameliorate a disorder responsive to the blockade of calcium channels, and particularly N-type calcium channels. Compounds of the present invention are especially useful for treating pain. 2. (canceled)4. The compound of claim 3 ,{'sup': 1', '2', '3', '4', '5, 'wherein Z is Z, Z, Z, Zor Z.'}5. The compound of claim 3 ,{'sup': '26', 'wherein Rare both hydrogen.'}6. The compound of claim 3 , wherein Ris hydrogen or unsubstituted benzyl.7. The compound of claim 1 , wherein{'sup': 3', '4', '1, 'a) Rand Rtogether form ═O and Z is Z; or'}{'sup': 3', '4', '2, 'b) Rand Rare both hydrogen, Z is Zand n is 0.'}9. The compound of claim 4 , wherein{'sup': 1', '5', '6', '7', '8, 'a) Z is Zand R, R, Rand Rare each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, cyano, amino, alkylamino, and dialkylamino; or'}{'sup': '2', 'claim-text': [{'sup': '9', 'i. Ris phenyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino; or'}, {'sup': '9', 'ii. Ris pyridyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, haloalkyl, halogen, haloalkoxy, and alkoxy; or'}], 'b) Z is Zand'}{'sup': '3', 'claim-text': [{'sup': '10', 'i. Ris phenyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and alkylcarbonylamino; or'}, {'sup': '10', 'ii. Ris 1,2,3,4-tetrahydroquinolinyl or 1,2,3,4- ...

Spirocyclic nitriles as protease inhibitors

The invention relates to substituted carbo- and heterocyclic spiro compounds of the formula Ia which inhibit thiol proteases, to processes for their preparation and to the use thereof as medicaments. 2. A pharmaceutical composition comprising a therapeutically effective amount of the compound of or a physiologically tolerated salt thereof and a pharmaceutically acceptable carrier.4. The method of claim 3 , wherein the condition or disorder is osteoarthritis.5. The method of claim 3 , wherein the condition or disorder is bone loss. This application is a continuation of U.S. application Ser. No. 13/248,366, filed Sep. 29, 2011, which is a divisional of U.S. application Ser. No. 12/277,880, filed Nov. 25, 2008, which is a continuation of International Application No. PCT/EP2007/004550, filed May 23, 2007, which are incorporated herein by reference in their entirety; and claims the benefit of priority of German Patent Application No. 102006025630.1, filed Jun. 1, 2006.The invention relates to substituted carbo- and heterocyclic spiro compounds of the formula Ia which inhibit thiol proteases, to processes for their preparation and to the use thereof as medicaments.Proteolytic enzymes, known as proteases and peptidases, are very important enzymes which make up about 2% of the genes in the human organism, pathogenic microorganisms and also other life forms. Their particular significance is that they influence many physiological processes by playing an important role in the activation, synthesis or degradation of other proteins. This inevitably gives rise to a crucial regulatory function starting at conception, birth, growth, maturation, aging, diseases up to death.The balance of the different processes is of crucial significance for the life and survival of the organism. When there is an imbalance of protease-catalyzed processes as a result of endogenous or exogenous factors such as genetic predisposition or environmental factors, massive disruption can occur in the normal ...

GLUCOCEREBROSIDASE MODULATORS AND USES THEREOF

The invention provides compounds for modulating glycosidases, prodrugs of the compounds, and pharmaceutical compositions including the compounds or prodrugs of the compounds. 2. The method of wherein the compound is one or more of the compounds described in Table 1.4. The method of wherein the condition is Parkinson's disease claim 3 , Dementia with Lewy bodies claim 3 , Multiple system atrophy claim 3 , Pick's disease claim 3 , Corticobasal degeneration claim 3 , Alzheimer's disease claim 3 , Amyotrophic lateral sclerosis claim 3 , Amyotrophic lateral sclerosis with cognitive impairment claim 3 , Argyrophilic grain dementia claim 3 , Bluit disease claim 3 , Dementia pugilistica claim 3 , Diffuse neurofibrillary tangles with calcification claim 3 , Down's syndrome claim 3 , Familial British dementia claim 3 , Familial Danish dementia claim 3 , Frontotemporal dementia with parkinsonism linked to chromosome 17 claim 3 , Gerstmann-Straussler-Scheinker disease claim 3 , Guadeloupean parkinsonism claim 3 , Hallevorden-Spatz disease claim 3 , neurodegeneration with brain iron accumulation type 1 claim 3 , Myotonic dystrophy claim 3 , Multi-infarct dementia claim 3 , Niemann-Pick disease type C claim 3 , Pallido-ponto-nigral degeneration claim 3 , Parkinsonism-dementia complex of Guam claim 3 , Post-encephalitic parkinsonism claim 3 , Prion diseases claim 3 , Creutzfeldt-Jakob Disease claim 3 , Variant Creutzfeldt-Jakob Disease claim 3 , Fatal Familial Insomnia claim 3 , Kuru claim 3 , Progressive supercortical gliosis claim 3 , Progressive supranuclear palsy claim 3 , Richardson's syndrome claim 3 , Subacute sclerosing panencephalitis claim 3 , Tangle-only dementia claim 3 , Huntington's disease claim 3 , Schizophrenia claim 3 , Mild Cognitive Impairment claim 3 , Neuropathy claim 3 , or Glaucoma.5. The method of wherein the condition is Parkinson's disease.6. The method of wherein the condition is Gaucher's disease.7. The method of wherein the compound is one or more of ...

Morphan And Morphinan Analogues, And Methods Of Use

The present application relates to analogues of morphan and morphinan, compositions thereof, and methods for treating a disease or condition comprising administering an effective amount of the compounds or compositions to a subject in need thereof. 19-. (canceled)11. The compound of claim 10 , wherein Ris C-Calkenyl or cycloalkyl.12. The compound of claim 10 , wherein Rand R claim 10 , together with the carbon atoms to which they are attached claim 10 , form a 6-membered unsubstituted carbocyclic ring or a 6-membered carbocyclic ring substituted with a hydroxyl or a ketone.13. The compound of claim 10 , wherein Rand R claim 10 , taken together with the carbon atom to which they are attach to claim 10 , form a C═O group.14. The compound of claim 10 , wherein Ris substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N claim 10 , O and S.16. The compound of claim 15 , wherein Ris cyclopropyl.17. The compound of claim 15 , wherein X is H or hydroxyl.18. The compound of claim 15 , wherein Y and Z are each claim 15 , independently claim 15 , H or hydroxyl claim 15 , or alternatively claim 15 , Y and Z claim 15 , together with the carbon atom to which they are attached claim 15 , form C═O.19. The compound of claim 15 , wherein Ris —C(O)NH.2128-. (canceled)29. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of .30. A method of treating a depressive symptom in a subject in need thereof claim 10 , the method comprising administering to the subject an effective amount of a compound of claim 10 , wherein the compound is a μ opioid receptor agonist having an Emax of 5% to 45% in a GTPγS binding assay.31. (canceled)32. The method of claim 30 , wherein said agonist has a low risk of opioid dependence claim 30 , opioid addiction claim 30 , and/or symptoms of opioid withdrawal.33. A method of treating a depressive symptom in a subject in need thereof claim 10 , the method comprising ...

CHROMANE, ISOCHROMANE AND DIHYDROISOBENZOFURAN DERIVATIVES AS mGluR2-NEGATIVE ALLOSTERIC MODULATORS, COMPOSITIONS, AND THEIR USE

The present invention provides certain substituted chromane, isochromane, and dihydroisobenzofuran compounds of formula (I): 130-. (canceled)321. The composition of claim , wherein the additional therapeutic agent is an acetylcholinesterase inhibitor.331. The composition of claim , wherein the acetylcholinesterase inhibitor is donepezil.35. The composition of claim 34 , wherein the additional therapeutic agent is an acetylcholinesterase inhibitor.365. The composition of claim claim 34 , wherein the acetylcholinesterase inhibitor is donepezil.38. The method of claim 37 , wherein the treating is for Alzheimer's Disease.39. The method of claim 38 , wherein the treating is for mood disorder.40. The method of claim 39 , wherein the mood disorder is depression.41. The method of claim 38 , further comprising administration of an acetylcholinesterase inhibitor.42. The method of claim 41 , wherein the acetylcholinesterase inhibitor is donepezil.44. The method of claim 43 , wherein the treating is for Alzheimer's Disease.45. The method of claim 43 , wherein the treating is for mood disorder.46. The method of claim 45 , wherein the mood disorder is depression.47. The method of claim 44 , further comprising administration of an acetylcholinesterase inhibitor.48. The method of claim 47 , wherein the acetylcholinesterase inhibitor is donepezil. The invention is directed to certain chromane, isochromane, and dihydroisobenzofuran derivatives, their salts, pharmaceutical compositions comprising them and their use in therapy of the human body. The compounds of the invention have been found to modulate the metabotropic glutamate receptor 2 (mGluR2), and hence are expected to be useful in the treatment of Alzheimer's Disease and other diseases mediated by the mGuR2 receptor.The metabotropic glutamate receptors are known to contain one or more allosteric sites, which may alter the affinity with which glutamate and other metabotropic glutamate (mGuR) ligands bind to the primary binding ...

OPIOID AGONISTS AND USES THEREOF

Provided are compounds, including those of Formula I; and pharmaceutically acceptable salts and solvates thereof. The compounds described herein relate to and/or have application(s) in (among others) the fields of drug discovery, pharmacotherapy, physiology, organic chemistry and polymer chemistry. 2. The compound of claim 1 , wherein Ris hydrogen.3. The compound of any one of the preceding claims claim 1 , wherein Ris alkyl.4. The compound of any one of the preceding claims claim 1 , wherein Ris cyclopropylmethyl.5. The compound of any one of the preceding claims claim 1 , wherein G is O and represents a double bond.6. The compound of any one of the preceding claims claim 1 , wherein Ris hydrogen.7. The compound of any one of the preceding claims claim 1 , wherein Ris selected from optionally substituted alkyl claim 1 , optionally substituted amino claim 1 , and —X-POLY.8. The compound of any one of the preceding claims claim 1 , wherein Ris optionally substituted amino.9. The compound of any one of the preceding claims claim 1 , wherein Ris amino substituted with an optionally substituted aryl or optionally substituted alkyl.10. The compound of any one of the preceding claims claim 1 , wherein Ris amino substituted with an optionally substituted phenyl.12. The compound of claim 11 , wherein q is 1.13. The compound of any one or claim 11 , wherein X is —NH—.14. The compound of any one of or claim 11 , wherein X is —O—.15. The compound of any one of to claim 11 , wherein POLY is a poly(alkylene oxide) oligomer.16. The compound of any one of to claim 11 , wherein POLY is a poly(ethylene oxide) oligomer.17. The compound of any one of to claim 11 , wherein POLY is capped with an optionally substituted alkyl.18. The compound of any one of to claim 11 , wherein POLY is capped with a methyl claim 11 , trifluoromethyl claim 11 , or methyl substituted with a carboxy group.20. The compound of claim 19 , wherein X is —O—.21. The compound of claim 19 , wherein X is —NH—.22. ...

INHIBITING FATTY ACID SYNTHASE (FASN)

The present disclosure is directed to inhibitors of FASN. The compounds can be useful in the treatment of disease or disorders associated with the inhibition of FASN. For instance, the disclosure is concerned with compounds and compositions for inhibition of FASN, methods of treating, preventing, or ameliorating diseases or disorders associated with the inhibition of FASN, and methods of synthesis of these compounds. 2. The method of claim 1 , wherein said treating the compound of formula (A) with the compound of formula (B) is performed in the presence of a palladium catalyst and a base.14. The method of claim 12 , wherein said converting the compound of formula (C) to the compound of formula (VII-A) comprises:coupling the compound of formula (C) with 1-hydroxycyclopropane-1-carboxylic acid to afford the compound of formula (VII-A). This application is a continuation of U.S. patent application Ser. No. 16/598,481, filed Oct. 10, 2020, which claims the benefit of U.S. Provisional Application No. 62/744,071, filed on Oct. 10, 2018, both of which are incorporated by reference in their entirety.The present disclosure relates to novel chemical compositions for inhibiting fatty acid synthase (FASN).Non-alcoholic steatohepatitis (NASH) is a chronic liver disease with varying degrees of inflammation and fibrosis that can progress to cirrhosis and end-stage liver complications. The disease affects greater than 16 million people in the US and is the second leading cause of liver transplants in the US. Moreover, NASH is a strong predictor for type 2 diabetes, cardiovascular disease and end-stage kidney disease. There are no pharmacological agents currently approved for the treatment of NASH, which represents a substantial healthcare burden. The pathogenesis of NASH has been associated with obesity or aberrant metabolic syndrome. Consistent with a proposed role for increased de novo lipogenesis (DNL) as a mediator of steatosis and liver injury, FASN expression is significantly ...

Morphinan Compounds

This disclosure relates to novel morphinan compounds and their derivatives, pharmaceutically acceptable salts, solvates, and hydrates thereof. This disclosure also provides compositions comprising a compound of this disclosure and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a σreceptor agonist that also has NMDA antagonist activity. 111-. (canceled)13. The method of claim 12 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.14. The method according to or claim 12 , further comprising administering a second therapeutic agent useful in the treatment or prevention of autism.15. The method of claim 14 , wherein the second therapeutic agent is selected from quinidine claim 14 , quinidine sulfate claim 14 , oxycodone claim 14 , and gabapentin.17. The separate dosage forms of claim 16 , wherein any atom not designated as deuterium is present at its natural isotopic abundance in the compound or pharmaceutically acceptable salt thereof. This application is a continuation of U.S. patent application Ser. No. 12/112,936, filed Apr. 30, 2008, which claims the benefit of priority under 35 U.S.C. §119 to U.S. Provisional Application Ser. Nos. 60/915,130, filed May 1, 2007, 60/916,662, filed May 8, 2007, and 60/976,044, filed Sep. 28, 2007, the entire contents of which are incorporated by reference in their entirety herein.This disclosure relates to novel morphinan compounds and their derivatives, pharmaceutically acceptable salts, solvates, and hydrates thereof. This disclosure also provides compositions comprising a compound of this disclosure and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a σreceptor agonist that also has NMDA antagonist activity.Dextromethorphan is currently one of the most widely used antitussives. Also known by the chemical name (+)-3-methoxy-17-methyl-(9α,13α, ...

NOVEL CARBO- AND HETEROCYCLIC SPIRO COMPOUNDS AS DONOR MATERIALS FOR ORGANIC PHOTOVOLTAICS AND THEIR PREPARATION

The subject invention provides compositions of and methods of using carbo- and heterocyclic spiro compounds as donor materials for organic photovoltaic (OPV) devices. In preferred embodiments, spiro compounds comprising triarylamine and derivatives thereof demonstrate effective hole-transporting properties in OPV devices, achieving up to 5.46% of power conversion efficiency. Advantageously, preferred compounds provided herein are thermally stable and volatile enough to form thin films for the photoactive layer of an OPV device by vacuum deposition or by spin-coating. 2. The compound according to claim 1 , wherein A claim 1 , B claim 1 , C claim 1 , and D are claim 1 , independently claim 1 , 5- or 6-membered rings selected from benzenes claim 1 , pyridines claim 1 , thiophenes claim 1 , furans claim 1 , fused-thiophenes claim 1 , pyrazoles claim 1 , pyrimidines claim 1 , pyrroles claim 1 , selenophenes claim 1 , tellurophenes claim 1 , benzimidazoles claim 1 , benzofurans claim 1 , benzothiazoles claim 1 , benzoxazoles claim 1 , benzophospholes claim 1 , indoles claim 1 , indanes claim 1 , naphthalenes claim 1 , anthracenes claim 1 , pyrenes claim 1 , thiazoles claim 1 , pyrans claim 1 , thiapyrans claim 1 , carbazoles claim 1 , dibenzothiophenes claim 1 , dibenzofurans claim 1 , dibenzosiloles claim 1 , fluorenes claim 1 , and dibenzophospholes claim 1 , each being optionally substituted.3. The compound according to claim 1 , comprising one or more of D claim 1 , D claim 1 , D claim 1 , and D claim 1 , wherein D claim 1 , D claim 1 , D claim 1 , and Dare independently selected from optionally substituted functional groups of alkylaminos claim 1 , arylamines claim 1 , thiophenes claim 1 , oligo-thiophenes claim 1 , fused-thiophenes claim 1 , fluorenes claim 1 , dibenzothiophenes claim 1 , dibenzofurans claim 1 , and dibenzophospholes.4. The compound according to claim 1 , wherein X is present and X is a carbon atom or a heteroatom claim 1 , each being optionally ...

NOVEL COMPOUND AND ORGANIC ELECTRONIC DEVICE USING THE SAME

A novel compound is disclosed, which comprises: a 7-membered ring segment, which is formed by a cis-stilbene segment and a bridge atom with four bonds; and an acridine segment connecting to the bridge atom of the 7-membered ring segment. In addition, an organic electronic device is also disclosed, and an organic layer therein comprises the novel compound of the present invention. 1. A compound comprising:a 7-membered ring segment, which is formed by a cis-stilbene segment and a bridge atom with four bonds; andan acridine segment connecting to the bridge atom of the 7-membered ring segment.2. The compound of claim 1 , wherein the bridge atom is C or Si.4. The compound of claim 3 , wherein Rand Rare the same.5. The compound of claim 3 , wherein Rand Rare —NRR claim 3 , and Ris aryl claim 3 , and Ris C-Calkyl or aryl.6. The compound of claim 5 , wherein each of Rand Rindependently is phenyl claim 5 , naphthyl claim 5 , or anthryl unsubstituted or substituted with C-Calkyl claim 5 , C-Calkoxy or —CN.10. The compound of claim 9 , wherein X is H claim 9 , methyl claim 9 , ethyl claim 9 , methoxy claim 9 , or ethoxy.11. The compound of claim 3 , wherein Rand Rare Br claim 3 , pyridyl phenyl claim 3 , naphthyl claim 3 , anthryl or carbazoyl.12. The compound of claim 3 , wherein Rand Rare phenyl unsubstituted or substituted with methoxy claim 3 , ethoxy claim 3 , or —CN.13. The compound of claim 3 , wherein Rand Rare —R-R claim 3 , in which Ris phenylene claim 3 , Ris phenyl unsubstituted or substituted with methoxy claim 3 , ethoxy claim 3 , or —CN.15. The compound of claim 3 , having glass transition temperatures (T) ranged from 118° C. to 163° C. claim 3 , decomposition temperatures (T) ranged from 400° C. to 465° C. and/or oxidation potentials ranged from 0.06 V to 0.87 V or the reduction potential ranged from −1.89 to −2.32 V.16. The compound of claim 3 , which is applied to an organic light emitting device claim 3 , an organic solar cell device claim 3 , an organic ...

Morphan and Morphinan Analogues, and Methods of Use

The present application relates to analogues of morphan and morphinan, compositions thereof, and methods for treating a disease or condition comprising administering an effective amount of the compounds or compositions to a subject in need thereof. 2. (canceled)3. (canceled)4. (canceled)7. (canceled)8. (canceled)9. (canceled)11. (canceled)12. (canceled)13. (canceled)14. (canceled)16. (canceled)17. (canceled)18. (canceled)19. (canceled)21. The compound of claim 1 , wherein the compound is a μ opioid receptor agonist having an Emax of 5% to 45% in a GTPγS binding assay.22. The compound of claim 21 , wherein the Emax is 15% to 35% in a GTPγS binding assay.23. (canceled)24. The compound of claim 1 , having a maximal dopamine efflux in the nucleus accumbens of 125% to 300% over baseline in a rat.25. The compound of claim 24 , having a maximal dopamine efflux in the nucleus accumbens of 200% to 300% over baseline in a rat.26. The compound of claim 1 , wherein the compound does not attenuate thermal pain in a rodent hot plate model when administered at a dose of at least 1 mg/kg.27. The compound of claim 26 , wherein the compound does not attenuate thermal pain in a rodent hot plate model when administered at a dose of at least 3 mg/kg.28. The compound of claim 26 , wherein the compound does not attenuate thermal pain in a rodent hot plate model when administered at a dose of 10 mg/kg.29. (canceled)30. A method of treating a depressive symptom in a subject in need thereof claim 26 , the method comprising administering to the subject an effective amount of a μ opioid receptor agonist that exhibits an Emax of 5% to 45% in a GTPγS binding assay.31. (canceled)32. (canceled)33. A method of treating a depressive symptom in a subject in need thereof claim 26 , the method comprising administering to the subject an effective amount of a compound having a maximal dopamine efflux in the nucleus accumbens of 125% to 300% over base line in a rat.34. (canceled)35. A method of treating a ...

BICYCLIC ROR-GAMMA MODULATORS

Described herein are retinoic acid related-related orphan nuclear receptor (ROR) modulators and methods of utilizing ROR-gamma modulators in the treatment of diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds. 11. The compound of any one of - , or a pharmaceutically acceptable salt , solvate , or stereoisomer thereof , wherein X is —NR— or —C(R)(R)—.12. The compound of any one of - , or a pharmaceutically acceptable salt , solvate , or stereoisomer thereof , wherein Q is attached to the ring carbon atoms at a and b.13. The compound of any one of - , or a pharmaceutically acceptable salt , solvate , or stereoisomer thereof , wherein Q is attached to the ring carbon atoms at c and d.14. The compound of any one of - , or a pharmaceutically acceptable salt , solvate , or stereoisomer thereof , wherein Q is attached to the ring carbon atoms at a and c.15. The compound of any one of - , or a pharmaceutically acceptable salt , solvate , or stereoisomer thereof , wherein Q is attached to the ring carbon atoms at b and d.19. The compound of any one of - , or a pharmaceutically acceptable salt , solvate , or stereoisomer thereof , wherein each Rand each Rare hydrogen.20. The compound of any one of - , or a pharmaceutically acceptable salt , solvate , or stereoisomer thereof , wherein t is 1 , 2 , or 3.21. The compound of any one of - , or a pharmaceutically acceptable salt , solvate , or stereoisomer thereof , wherein t is 1.22. The compound of any one of - , or a pharmaceutically acceptable salt , solvate , or stereoisomer thereof , wherein Ris C-Calkyl , C-Cheteroaryl , (C-Cheteroaryl)-C-Calkylene- , —S(O)R , —C(O)R , —C(O)OR , or —C(O)—C-Calkylene-OR , wherein C-Cheteroaryl and (C-Cheteroaryl)-C-Calkylene- are optionally substituted with 1 or 2 groups each independently selected from halo , C-Calkyl , C-Chaloalkyl , and hydroxyl.23. The compound of any one of - , or a pharmaceutically acceptable salt , solvate ...

BRIDGED BICYCLIC HETEROARYL SUBSTITUTED TRIAZOLES USEFUL AS AXL INHIBITORS

Bridged bicyclic heteroaryl substituted triazoles and pharmaceutical compositions containing the compounds are disclosed as being useful in inhibiting the activity of the receptor protein tyrosine kinase Axl. Methods of using the compounds in treating diseases or conditions associated with Axl activity are also disclosed. 2. The compound of selected from the group consisting of:{'sup': '3', '1-(6,9-ethano-4-phenyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-2-yl)-N-(4-(4-(pyrrolidin-1-yl)piperidinyl)-3-fluorophenyl)-1H-1,2,4-triazole-3,5-diamine;'}{'sup': '3', '1-(1,4-ethano-8-(4-fluorophenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N-(4-(4-(pyrrolidin-1-yl)piperidinyl)-3-fluorophenyl)-1H-1,2,4-triazole-3,5-diamine;'}{'sup': '3', '1-(1,4-ethano-8-(3-fluorophenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N-(4-(4-(pyrrolidin-1-yl)piperidinyl)-3-fluorophenyl)-1H-1,2,4-triazole-3,5-diamine;'}{'sup': '3', '1-(1,4-ethano-8-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N-(4-(4-(pyrrolidin-1-yl)piperidinyl)-3-fluorophenyl)-1H-1,2,4-triazole-3,5-diamine;'}{'sup': '3', '1-(1,4-ethano-8-(3-methoxyphenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N-(4-(4-(pyrrolidin-1-yl)piperidinyl)-3-fluorophenyl)-1H-1,2,4-triazole-3,5-diamine; and'}{'sup': '3', '1-(1,4-ethano-8-(2-methylphenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N-(4-(4-(pyrrolidin-1-yl)piperidinyl)-3-fluorophenyl)-1H-1,2,4-triazole-3,5-diamine.'}6. The compound of selected from the group consisting of:{'sup': '3', '1-(4-chloro-5,8-ethano-5,6,7,8-tetrahydrophthalazine-1-yl)-N-(4-(4-(pyrrolidin-1-yl)piperidinyl)-3-fluorophenyl)-1H-1,2,4-triazole-3,5-diamine;'}{'sup': '3', '1-(4-(2-chlorophenyl)-5,8-ethano-5,6,7,8-tetrahydrophthalazine-1-yl)-N-(4-(4-(pyrrolidin-1-yl)piperidinyl)-3-fluorophenyl)-1H-1,2,4-triazole-3,5-diamine;'}{'sup': '3', '1-(4-(3-cyanophenyl)-5,8-ethano-5,6,7,8-tetrahydrophthalazine-1-yl)-N-(4-(4-(pyrrolidin-1-yl)piperidinyl)-3-fluorophenyl)-1H-1,2,4-triazole-3,5-diamine;'}{'sup ...

PROCESS FOR THE PREPARATION OF EXO-TERT-BUTYL N-(3-AZABICYCLO[3.2.1]OCTAN-8-YL)CARBAMATE

The present invention relates to a process for the preparation of a compound (I) or pharmaceutically acceptable salt thereof, which is useful as the key intermediate for the synthesis of compounds for prophylaxis and treatment of a disease associated with the deposition of β-amyloid in the brain, in particular Alzheimer's disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome. 2. A process according to claim 1 , characterized in that the formation of the compound (IV) in step b) is performed in the presence of a reducing reagent at 0° C.-70° C. claim 1 , wherein the reducing reagent is selected from Na claim 1 , Pd/c and Raney-Ni; particularly the reaction is performed in the presence of Raney-Ni at 20° C.-30° C.3. A process according to or claim 1 , characterized in that the amount of (R)-(−)-Mandelic acid used in step c) is 0.1-2.0 eq. claim 1 , particularly 0.6 eq.4. A process according to any one of to claim 1 , characterized in that the compound (VI) synthesized in step d) is purified through recrystallization claim 1 , which was performed in a solvent claim 1 , wherein the solvent is selected from n-heptane claim 1 , hexane and petroleum ether; particularly the solvent is n-heptane.5. A process according to any one of to claim 1 , characterized in that the reduction reaction in step d) is performed at 20° C.-100° C. claim 1 , particularly at 65° C.-75° C. The present invention relates to a process for the preparation of a compound (I),or pharmaceutically acceptable salt thereof, which is useful as the key intermediate for the synthesis of compounds for prophylaxis and treatment of a disease associated with the deposition of β-amyloid in the brain, in particular Alzheimer's disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi- ...

G-protein biased opioid receptor agonist/analgesics with reduced arrestin recruitment

In some aspects, the present disclosure provides compounds of the formula: wherein the variables are as defined herein. In some embodiments, these compounds may be used to reduce the pain of a patient. These compounds may be used in pain relief and show an improved pharmaceutical profile relative to other commonly used opiates and opioid derivatives.

SPIRO-COMPOUNDS AS SIP MODULATORS

The invention relates to heterocyclic compounds of formula (I) as SIP modulators, pharmaceutical compositions comprising such compounds, and uses thereof in the treatment or alleviation of diseases or disorders mediated by an SIP receptor. 2. A compound according to wherein m and n are both 0 or both 1.4. A compound according to wherein R1 is selected from the group consisting of -1 claim 3 ,3-cyclobutylene-R2 and —(C1-3)alkylene-R2 claim 3 , wherein the (C1)alkyl is unsubstituted claim 3 , and the (C2)alkyl and the (C3)alkyl are substituted with up to two CHgroups claim 3 , with (CH)to form a cyclopropyl moiety or with (CH)to form a cyclobutyl moiety.5. A compound according to wherein X is CH.6. A compound according to wherein R3 is selected from the group consisting of:(C3-6)cycloalkyl, preferably cyclohexyl, optionally substituted with (C1-4) alkyl; halogen,', 'cyano,', '(C1-4)alkyl optionally substituted with one or more fluoro atoms,', '(C1-4)alkoxy optionally substituted with one or more fluoro atoms or with (C3-6)cycloalkyl,', '(C3-5)cycloalkoxy optionally substituted with one or more fluoro atoms; and', '(C3-6)cycloalkyl optionally substituted with (C1-4)alkyl, (C1-4)alkoxy or a halogen atom,, 'monocyclic heterocycle, preferably oxanyl or pyridyl, optionally substituted with 1 or 2 substituents independently selected from the group consisting ofindanyl, optionally substituted with one or two halogen atoms8-10 membered fused bicyclic group, preferably preferably 2,3-dihydrobenzofuranyl, indanyl, indoly or 1,3-dioxaindanyl, optionally substituted with one or two halogen atoms; halogen,', 'cyano,', '(C1-4)alkyl optionally substituted with one or more fluoro atoms,', '(C1-4)alkoxy optionally substituted with one or more fluoro atoms or with (C3-6)cycloalkyl,', '(C3-5)cycloalkoxy optionally substituted with one or more fluoro atoms; and', '(C3-6)cycloalkyl optionally substituted with (C1-4)alkyl, (C1-4)alkoxy or a halogen atom., 'phenyl optionally substituted ...

MORPHINAN COMPOUNDS

This invention relates to novel morphinan compounds and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a σreceptor agonist that also has NMDA antagonist activity. 1. (canceled)3. The method of claim 2 , wherein the subject is suffering from or susceptible to diabetic neuropathic pain.4. The method of claim 2 , wherein the subject is suffering from or susceptible to epileptic seizures.5. The method of claim 2 , wherein the neurological disorder is schizophrenia. This application is a continuation of U.S. patent application Ser. No. 14/208,968, filed Mar. 13, 2014, which is a continuation of U.S. patent application Ser. No. 13/119,905, filed Jul. 1, 2011 (now U.S. Pat. No. 8,710,072), which is a National Stage application under 35 U.S.C. §371 of International Application No. PCT/US2009/057476, filed Sep. 18, 2009, which claims priority to U.S. Provisional Application Ser. No. 61/098,511, filed Sep. 19, 2008, which are incorporated by reference herein in their entirety.This invention relates to novel morphinan compounds and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a sigma-1 receptor agonist that also has NMDA antagonist activity.Dextromethorphan, also known by its chemical name (+)-3-methoxy-17-methyl-(9α,13α,14α)-morphinan, is currently one of the most widely used antitussives.In addition to the physiological activity noted above, dextromethorphan is also an agonist of the σ2 receptor, an N-methyl-D-aspartate (NMDA) antagonist, and an α3β4 nicotinic receptor antagonist. Dextromethorphan inhibits neurotransmitters, such as glutamate, from activating receptors ...

HERBICIDAL COMPOUNDS

The present invention relates to compounds of Formula (I), wherein R1, R2, R3, R4 and G are as defined herein. The invention further relates to herbicidal compositions which comprise a compound of Formula (I), to their use for controlling weeds, in particular in crops of useful plants. 2. A compound of according to claim 1 , wherein Ris 1-propynyl claim 1 , Ris methyl or methoxy and Ris methyl or methoxy.3. A compound according to claim 1 , wherein Ris methyl.4. A compound according to claim 1 , wherein Ris methyl.5. A compound according to claim 1 , wherein Ris methoxy.6. A compound according to claim 1 , wherein Ris —S(O)NRR.7. A compound according to claim 1 , wherein Ris —S(O)(═NR)R.8. A compound according to claim 1 , wherein G is hydrogen.9. A compound according to claim 1 , wherein G is —C(O)C-Calkyl.10. A compound according to claim 1 , wherein G is —C(O)—O—C-Calkyl.11. A herbicidal composition comprising a compound of Formula (I) according to and an agriculturally acceptable formulation adjuvant.12. A herbicidal composition according to claim 11 , further comprising at least one additional pesticide.13. A herbicidal composition according to claim 12 , wherein the additional pesticide is a herbicide or herbicide safener.14. A method of controlling weeds at a locus comprising application to the locus of a weed controlling amount of a composition according to .15. A method of controlling weeds by applying a compound of Formula (I) as defined in . The present invention relates to novel herbicidal compounds, to processes for their preparation, to herbicidal compositions which comprise the novel compounds, and to their use for controlling weeds.Herbicidal cyclic dione compounds substituted by a phenyl which has an alkynyl-containing substituent are disclosed in, for example, WO2014/096289 and WO2015/197468. The present invention relates to novel herbicidal cyclohexanedione derivatives with improved properties.Thus, according to the present invention there is ...

DEXTRORPHAN PRODRUGS AND PROCESSES FOR MAKING AND USING THEM

The presently described technology provides compositions of one or more of oxoacids, polyethylene glycols, and/or vitamin compounds chemically conjugated to dextrorphan, (+)-17-methylmorphinan-3-ol), to form novel prodrugs and compositions of dextrorphan. 2. The compound of claim 1 , wherein Land Yare present claim 1 , Gis at least one oxoacid claim 1 , and m is 1-3.3. The compound of claim 1 , wherein Gis at least one oxoacid selected from the group consisting of aliphatic carboxylic acid claim 1 , aryl carboxylic acid claim 1 , dicarboxylic acid claim 1 , polycarboxylic acid claim 1 , standard amino acids claim 1 , non-standard amino acids claim 1 , and synthetic amino acids claim 1 , and combinations thereof.4. The compound of wherein Gis a combination of at least two oxoacids claim 3 , wherein at least one of the at least two oxoacids is selected from the group consisting of aliphatic carboxylic acid claim 3 , aryl carboxylic acid claim 3 , dicarboxylic acid claim 3 , and polycarboxylic acid claim 3 , and combinations thereof claim 3 , and at least one of the at least two oxoacids is selected from standard amino acids claim 3 , non-standard amino acids claim 3 , synthetic amino acids claim 3 , and combinations thereof.5. The compound of claim 4 , wherein the at least one of the at least two oxoacids is valine.8. The compound of claim 7 , wherein where Land Yare absent claim 7 , M is —(CRR) claim 7 , Gis at least one oxoacid claim 7 , and m is 1-3.9. The compound of claim 7 , wherein the at least one oxoacid is acetic acid.12. The compound of claim 11 , wherein at least one of Gand Gis at least one oxoacid.13. The compound of claim 12 , wherein Gand Gare each acetic acid.15. A composition wherein the composition comprises the compound of 39 or a pharmaceutically acceptable salt of the compound.16. A composition wherein the composition comprises the compound of or a pharmaceutically acceptable salt of the compound.17. The composition of claim 15 , wherein the ...

CYCLIC AMINE DERIVATIVES AS EP4 RECEPTOR ANTAGONISTS

There is described a novel group of cyclic amine derivative compounds, having an EPreceptor antagonistic activity and specifically pharmaceutical compounds which are useful for the treatment or alleviation of Prostaglandin E mediated diseases. 2. A cyclic amine compound of formula (I) according to wherein Ar is phenyl having in 4 position one substituent selected from fluorine claim 1 , cyano or trifluorormethyl.3. A cyclic amine compound of formula (I) according to wherein Ris hydrogen and Ris methyl or both Rand Rare fused together to form a cyclopropyl ring.5. A cyclic amine compound of formula (IB) according to wherein Ar is phenyl having in 4-position at least one substituent selected from the group consisting of: fluorine claim 4 , cyano and trifluoromethyl.6. A cyclic amine compound of formula (IB) according to wherein Rand Rare methyl or are linked together to form a cyclopropyl ring.7. A cyclic amine compound of formula (IB) according to anyone of wherein Ris hydrogen.8. A cyclic amine compound of formula (IB) according to wherein Rand Rare independently selected from hydrogen claim 4 , fluorine claim 4 , methyl or are fused together to form a cyclopropyl ring.9. A cyclic amine compound of formula (IB) according to wherein n is 1 and Rand Rare independently selected from hydrogen claim 4 , fluorine claim 4 , methyl.10. A cyclic amine compound of formula (IB) according to wherein n is 2 and Ar is phenyl substituted in 4 position with at least one substituent selected from the group consisting of: fluorine claim 4 , cyano and trifluoromethyl.11. A cyclic amine compound of formula (IB) according to wherein n is 2 claim 4 , both Rand Rare fluorine or are fused together to form a cyclopropyl ring.13. A cyclic amine compound of formula (IC) according to wherein Ar is phenyl having in 4-position at least one substituent selected from the group consisting of: fluorine claim 12 , cyano and trifluoromethyl.14. A cyclic amine compound of formula (IC) according to ...

COMPOSITIONS AND METHODS FOR THE TREATMENT OF RESPIRATORY DISORDERS

The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for the treatment of respiratory disorders may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of cough caused by minor throat and bronchial irritation (such as commonly accompanies the flu and common cold), as well as those resulting from inhaled particle irritants, upper respiratory infections, (pseudobulbar affect) in patients with amyotrophic lateral sclerosis and multiple sclerosis, neuropathic pain and pain associated with fibromyalgia. 2. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier.3. The pharmaceutical composition of claim 2 , wherein said pharmaceutical composition is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration claim 2 , delayed release or sustained release claim 2 , transmucosal claim 2 , syrup claim 2 , topical claim 2 , parenteral administration claim 2 , injection claim 2 , subdermal claim 2 , oral solution claim 2 , rectal administration claim 2 , buccal administration or transdermal administration.4. A method of treating respiratory disorders related diseases as the underlying etiology claim 3 , the method comprising administering to a patient in need thereof an effective amount of .5. The method of claim 4 , wherein the respiratory disorders as the underlying etiology is selected from cough caused by minor throat and bronchial irritation (such as commonly accompanies the flu and common cold) claim 4 , as well as those resulting from inhaled particle irritants claim 4 , upper respiratory infections claim 4 , ( ...

CHROMANE, ISOCHROMANE AND DIHYDROISOBENZOFURAN DERIVATIVES AS mGluR2-NEGATIVE ALLOSTERIC MODULATORS, COMPOSITIONS, AND THEIR USE

The present invention provides certain substituted chromane, isochromane, and dihydroisobenzofuran compounds of formula (I): 3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein{'sup': '2', 'sub': 3', '3', '2', '2', '2', '3', '2', '2', '3', '2', '2', '2', '2', '2', '3', '2', '2', '2', '2', '3', '2', '3', '2', '2', '2', '3', '2', '3', '2', '3, 'Ris selected from H, cyclopropyl, —CH, —CH(CH), —CH—OH, —CH—OCH, —CHF, —CHF, —CF, —CHCHF, —CHCHF, —CHCF, —CH—O—CHF, —CH—O—CHF, —CH(CH)—O—CHF, —CH(CH)—O—CHF, —CH—NH—CHCF, and —CH—N(CH)—CHCF;'}{'sup': '2A', 'Ris selected from H and methyl;'}{'sup': '3', 'Ris selected from H and methyl; and'}{'sup': '3A', 'Ris selected from H and methyl.'}4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein{'sup': 2', '2A, 'Rand Rare both methyl; and'}{'sup': 3', '3A, 'Rand Rare both H.'}8. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein:ring B is a moiety selected from the group consisting of phenyl, cyclopentyl, cyclohexyl, pyridinyl, pyrimidinyl, pyrazolyl, thienyl, thiazolyl, thiadiazolyl, isoxazolyl, oxadiazolyl and oxazolyl;n is 0, 1, 2, or 3, provided that the value of n does not exceed the maximum number of substitutable hydrogen atoms on ring B; and{'sup': '1', 'sub': 1', '6', '1', '6', '1', '6', '1', '6', '2', '1', '6', '1', '6', '2', '1', '6, 'each R(when present) is independently selected from the group consisting of halogen, —CN, —OH, —(C-C) alkyl, —O—(C-C) alkyl, —(C-C) haloalkyl, —O—(C-C) haloalkyl, cyclopropyl, cyclobutyl, —NH, —NH(C-C)alkyl, —N(C-Calkyl), —C(O)O(C-C) alkyl, and phenyl.'}9. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein:ring B is a moiety selected from the group consisting of: phenyl, pyrazolyl, pyridinyl, thienyl, isoxazolyl, oxadiazolyl and oxazolyl;n is 0, 1, or 2; and{'sup': '1', 'sub': 3', '2, 'each R(when present) is independently selected from ...

COMPOUNDS FOR ORGANIC LIGHT EMITTING DIODE MATERIALS

Described herein are molecules for use in organic light emitting diodes. Example compounds include molecules represented by structural formula (I). Values and example value of in the structural formula (I) are defined herein. 3. The molecule of claim 1 , wherein Xis SiRR claim 1 , BR claim 1 , O claim 1 , or S.4. The molecule of claim 3 , wherein Xis SiRRor BR.5. The molecule of claim 1 , wherein each instance of R claim 1 , R claim 1 , and Ris independently selected from H claim 1 , phenyl claim 1 , and Calkyl.6. The molecule of claim 1 , wherein each instance of Ris H or C-Calkyl.7. The molecule of claim 1 , wherein each of rings A claim 1 , B claim 1 , C claim 1 , and D contains no more than one nitrogen atom.8. The molecule of claim 1 , wherein at least two of rings A claim 1 , B claim 1 , C claim 1 , and D contain at least one nitrogen atom.9. The molecule of claim 8 , wherein at least three of rings A claim 8 , B claim 8 , C claim 8 , and D contain at least one nitrogen atom.10. The molecule of claim 9 , wherein each of rings A claim 9 , B claim 9 , C claim 9 , and D contains at least one nitrogen atom.11. The molecule of claim 1 , wherein Xis B-phenyl and Xis O claim 1 , S claim 1 , N-phenyl claim 1 , —C(CH)— claim 1 , —Si(CH)— claim 1 , —CH— claim 1 , —SiH— claim 1 , or a bond.12. The molecule of claim 1 , wherein Xis N-phenyl and Xis O claim 1 , C(O) claim 1 , B-phenyl claim 1 , —C(CH)— claim 1 , —Si(CH)— claim 1 , —CH— claim 1 , —SiH— claim 1 , or a bond.13. The molecule of claim 1 , wherein Xis C(O) and Xis N-phenyl claim 1 , B-phenyl claim 1 , O claim 1 , S claim 1 , or a bond.14. The molecule of claim 1 , wherein Xis O or S and Xis B-phenyl or C(O).16. A molecule represented by any one structural formula as shown in Table I.17. An organic light-emitting device containing:a first electrode;a second electrode; and{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'an organic layer disposed between the first electrode and the second electrode, wherein the ...

METHODS OF RESOLVING RACEMIC MIXTURE TO OBTAIN (-)-HUPERZINE A

A method of resolving a racemic mixture of (±)-Huperzine A to (−)-Huperzine A includes: separating the (−)-Huperzine A from the racemic mixture of (±)-Huperzine A by chiral high performance liquid chromatography (HPLC), the chiral HPLC being performed utilizing a mobile phase including a solution including an alcohol and one selected from dichloromethane, trichloromethane, and a mixture thereof, and the chiral HPLC being performed utilizing a chiral stationary phase including a polysaccharide derivative. 1. A method of resolving a racemic mixture of (±)-Huperzine A to (−)-Huperzine A , the method comprising:separating the (−)-Huperzine A from the racemic mixture of (±)-Huperzine A by chiral high performance liquid chromatography (HPLC),the chiral HPLC being performed utilizing a mobile phase comprising a solution comprising an alcohol and one selected from dichloromethane, trichloromethane, and a mixture thereof, andthe chiral HPLC being performed utilizing a chiral stationary phase comprising a polysaccharide derivative.2. The method of claim 1 , wherein the alcohol is selected from primary alcohols having 1 to 6 carbon atoms claim 1 , secondary alcohols having 1 to 6 carbon atoms claim 1 , and mixtures thereof.3. The method of claim 2 , wherein the alcohol comprises methanol claim 2 , ethanol claim 2 , isopropanol claim 2 , or a mixture thereof.4. The method of claim 1 , wherein a volume ratio of a volume of the one selected from dichloromethane claim 1 , trichloromethane claim 1 , and a mixture thereof to a volume of the alcohol is 8:1 to 1:8.5. The method of claim 4 , wherein the volume ratio of the volume of the one selected from dichloromethane claim 4 , trichloromethane claim 4 , and a mixture thereof to the volume of the alcohol is 4:1 to 1:4.6. The method of claim 5 , wherein the volume ratio of the volume of the one selected from dichloromethane claim 5 , trichloromethane claim 5 , and a mixture thereof to the volume of the alcohol is 2:8 to 5:8.7. The ...

Beta-Amyloid-Directed Multitarget Compounds For The Treatment Of Alzheimer's Disease

The compounds of formula (I), or its pharmaceutically acceptable salts, or any stereoisomer or mixture thereof, wherein: Ris a (C-C) alkyl radical; Rand Rare radicals independently selected from the group consisting of F, Cl and methyl Ris H or OH; A is a birradical selected from the group consisting of —(CH)— and —(CH)-phenyl-(CH)—; t is an integer from 0 to 1; and n is an integer from 8 to 15, are useful for the treatment of Alzheimer's disease. 2. The compound according to claim 1 , wherein Ris methyl claim 1 , Ris Cl claim 1 , t is 0 claim 1 , and Ris H.3. The compound according to claim 1 , wherein A is —(CH)— and n is an integer from 8 to 12.4. The compound according to claim 3 , wherein n is an integer from 8 to 9.5. The compound according to claim 1 , wherein A is —(CH)-phenyl-(CH)—.6. The compound according to claim 1 , which is selected from the following list:(±)-N-{8-[(3-chloro-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinolin-12-yl)amino]octyl}-9,10-dihydro-4,5-dihydroxy-9,10-dioxoanthracene-2-carboxamide;(±)-N-{9-[(3-chloro-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinolin-12-yl)amino]nonyl}-9,10-dihydro-4,5-dihydroxy-9,10-dioxoanthracene-2-carboxamide;(−)-(7S,11S)—N-{9-[(3-chloro-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinolin-12-yl)amino]nonyl}-9,10-dihydro-4,5-dihydroxy-9,10-dioxoanthracene-2-carboxamide;(+)-(7R,11R)—N-{9-[(3-chloro-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinolin-12-yl)amino]nonyl}-9,10-dihydro-4,5-dihydroxy-9,10-dioxoanthracene-2-carboxamide;(±)-N-{10-[(3-chloro-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinolin-12-yl)amino]decyl}-9,10-dihydro-4,5-dihydroxy-9,10-dioxoanthracene-2-carboxamide;(±)-N-{11-[(3-chloro-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinolin-12-yl)amino]undecyl}-9,10-dihydro-4,5-dihydroxy-9,10-dioxoanthracene-2-carboxamide; and(±)-N-{4-{[(3-chloro-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinolin-12-yl)amino]methyl} ...

GUANIDINE COMPOUNDS AND USE THEREOF

The present invention relates to guanidine compounds for inhibiting mitochondrial oxidative phosphorylation (OXPHOS) and use thereof. More specifically, the present invention relates to a pharmaceutical composition for preventing or treating a OXPHOS-related disease, particularly cancer by inhibiting mitochondrial oxidative phosphorylation and reprogramming cellular metabolism. 2. The compound of claim 1 , wherein Rand Rare hydrogen in Chemical formula 1.4. The compound of claim 1 , wherein claim 1 , in Chemical formula 1 claim 1 , Rand Rare taken together with N to which they are attached for forming 5 to 6-membered saturated or unsaturated heterocycloalkyl group and is substituted with halogen claim 1 ,{'sup': 3', '4, 'Rand Rare independently H,'}n is 0, 1 or 2, and{'sup': 5', '6', '7', '8', '9', '10', '11', '12', '11', '12, 'sub': 1', '4', '1', '4', '1', '4', '1', '3', '1', '3', '6', '10, 'Ris aryl group represented by Chemical formula 2 where R, R, R, R, and Rare independently H, halogen, C-Calkyl, C-Calkoxy, halolalkyl, C-Chaloalkoxy, SRor ORwhere Rand Rare independently C-Calkyl, C-Chaloalkyl, or C-Caryl, or are linked with an adjacent substituent to form of 5 to 6 membered saturated ring.'}5. The compound of claim 1 , wherein claim 1 , in Chemical formula 1 claim 1 , Rand Rare taken together with N to which they are attached for forming 5 to 6-membered saturated or unsaturated heterocycloalkyl group and is substituted with halogen claim 1 ,{'sup': 3', '4, 'Rand Rare independently H,'}n is 0, and{'sup': 5', '6', '7', '8', '9', '10, 'sub': 1', '4, 'Ris aryl group represented by Chemical formula 2 where R, R, R, Rand Rare independently C-Chaloalkoxy.'}6. A compound selected from the group consisting of the following compounds claim 1 , pharmaceutically acceptable salts claim 1 , pharmaceutically acceptable solvates and prodrug derivatives:N—(N-phenylcarbamimidoyl)-4,4-difluoropiperidine-1-carboximidamideN—(N-(5,6,7,8-teterhydronaphthalene-2-yl)carbamimidoyl)-4,4 ...

9-AMINOMETHYL SUBSTITUTED TETRACYCLINE COMPOUNDS

The present invention relates to 9-aminomethyl substituted tetracycline compounds represented by formula (I), or pharmaceutically acceptable salt, prodrug, solvate or isomer thereof, as well as a method for preparing these compounds and a pharmaceutical composition comprising the same. The present invention relates also to a use of these compounds in the preparation of a medicament for the treatment and/or prophylaxis of tetracycline drug-sensitive disease. 4. The compound of claim 3 , or pharmaceutically acceptable salt claim 3 , prodrug claim 3 , solvate or isomer thereof claim 3 ,wherein{'sup': 9a', '9b, 'claim-text': [{'sup': 9a', '9b, '(1) hydrogen, provided that Rand Rcan not be hydrogen at the same time,'}, {'sup': 1', 'c', 'c, 'sub': '1-4', '(2) cyclopropyl, cyclobutyl, 6- to 10-membered spirocyclic group, 6-membered endocyclic group or 6- to 10-membered saturated fused ring group, the above groups are unsubstituted or substituted by 1 to 3 substituent(s) which may be the same or different and selected from Q, and carbon(s) in said cyclopropyl, cyclobutyl, 6- to 10-membered spirocyclic group, 6-membered endocyclic group and 6- to 10-membered saturated fused ring group may be replaced by 1 to 3 atom(s) or group(s) which may be the same or different and selected from O, CO, N and NR, Rrepresents hydrogen or Calkyl,'}, {'sub': 1-4', '1-4', '1-4', '1-4', '1-4', '1-4, 'sup': 1', 'c', 'c', 'c, '(3) cyclobutylCalkyl, cyclopentylCalkyl, 6- to 10-membered spirocyclic group Calkyl, 6- to 9-membered endocyclic group Calkyl or 6- to 10-membered saturated fused ring group Calkyl, the above groups are unsubstituted or substituted by 1 to 3 substituent(s) which may be the same or different and selected from Q, and carbon(s) in said cyclobutyl, 6- to 10-membered spirocyclic group and 6- to 9-membered endocyclic group may be replaced by 1 to 3 atom(s) or group(s) which may be the same or different and selected from O, CO, N and NR, carbon(s) in said 6- to 10-membered ...

HERBICIDAL COMPOUNDS

The present invention relates to compounds of Formula (I), 5 wherein R, R, R, Rand G are as defined herein. The invention further relates to herbicidal compositions which comprise a compound of Formula (I), to their use for controlling weeds, in particular in crops of useful plants. 2. A compound of according to claim 1 , wherein Ris 1-propynyl claim 1 , Ris methyl or methoxy and Ris methyl or methoxy.3. A compound according to claim 1 , wherein Ris methyl.4. A compound according to claim 1 , wherein Ris methyl.5. A compound according to claim 1 , wherein Ris methyl.6. A compound according to claim 1 , wherein Ris —C(O)C(R)═N—O—R.7. A compound according to claim 1 , wherein Ris methyl.8. A compound according to claim 1 , wherein G is hydrogen.9. A compound according to claim 1 , wherein G is —C(O)C-Calkyl.10. A compound according to claim 1 , wherein G is —C(O)—O—C-Calkyl.11. A herbicidal composition comprising a compound of Formula (I) according and an agriculturally acceptable formulation adjuvant.12. A herbicidal composition according to claim 11 , further comprising at least one additional pesticide.13. A herbicidal composition according to claim 12 , wherein the additional pesticide is a herbicide or herbicide safener.14. A method of controlling weeds at a locus comprising application to the locus of a weed controlling amount of a composition according to .15. Use of a compound of Formula (I) as defined in as a herbicide. The present invention relates to novel herbicidal compounds, to processes for their preparation, to herbicidal compositions which comprise the novel compounds, and to their use for controlling weeds.Herbicidal cyclic dione compounds substituted by a phenyl which has an alkynyl-containing substituent are disclosed in, for example, WO2014/096289 and WO2015/197468. The present invention relates to novel herbicidal cyclohexanedione derivatives with improved properties.Thus, according to the present invention there is provided a compound of Formula ...

CARBOXAMIDE BIOISOSTERES OF OPIATES

A compound of formula I is disclosed. 8. A compound according to wherein one of Rand Ris in the para position relative to B and the other of Rand Ris hydrogen.9. A compound according to claim 1 , wherein Aris phenyl and one of Ror Ris in the para position relative to B.11. A pharmaceutical formulation comprising a compound according to and a pharmaceutically acceptable carrier.12. A method of preventing or treating a condition or disease associated with binding opioid receptors in a patient in need thereof claim 1 , comprising the step of administering to said patient a composition comprising an effective amount of a compound according to .13. A method according to wherein said disease or condition is chosen from the group consisting of pain claim 12 , pruritis claim 12 , diarrhea claim 12 , irritable bowel syndrome claim 12 , gastrointestinal motility disorder claim 12 , obesity claim 12 , respiratory depression claim 12 , convulsions claim 12 , coughing claim 12 , hyperalgesia claim 12 , inflammation claim 12 , osteoarthritis and drug addiction.14. A method according to claim 13 , wherein the condition is pain and the composition further comprises an effective amount of an opioid.15. A method according to claim 13 , wherein the condition is osteoarthritis and the composition further comprises an effective amount of an opioid.18. A compound according to wherein said Rand Rare hydrogen.19. A compound according to wherein Ris —OH claim 1 , —CHO claim 1 , —CONH—CON(H)CHCONH claim 1 , —CON(H)CHCHCONH claim 1 , —CON(H)CHCOOH claim 1 , or —CON(H)CHCHCOOH; or Rand Rtogether with the atoms to which they are attached forms a —OCHO— fused ring.20. A compound according to wherein Ris H. This application is a continuation application of U.S. patent application Ser. No. 13/857,588, filed Apr. 5, 2013, now allowed, which is a divisional application of U.S. patent application Ser. No. 13/069,104, filed Mar. 22, 2011, now U.S. Pat. No. 8,436,175. U.S. patent application Ser. No. ...

CARBOXAMIDE BIOISOSTERES OF OPIATES

A compound of formula I is disclosed. 8. A compound according to wherein Ris in the para position relative to B and Ris hydrogen.9. A compound according to claim 1 , wherein Aris phenyl and one of Ror Ris in the para position relative to B.11. A pharmaceutical formulation comprising a compound according to and a pharmaceutically acceptable carrier.12. A method of preventing or treating a condition or disease associated with binding opioid receptors in a patient in need thereof claim 1 , comprising the step of administering to said patient a composition comprising an effective amount of a compound according to .13. A method according to wherein said disease or condition is chosen from the group consisting of pain claim 12 , pruritis claim 12 , diarrhea claim 12 , irritable bowel syndrome claim 12 , gastrointestinal motility disorder claim 12 , obesity claim 12 , respiratory depression claim 12 , convulsions claim 12 , coughing claim 12 , hyperalgesia claim 12 , inflammation claim 12 , osteoarthritis and drug addiction.14. A method according to wherein said drug addiction is selected from heroin claim 13 , cocaine claim 13 , nicotine claim 13 , amphetamine and alcohol addiction.15. A method according to claim 13 , wherein the condition is pain and the composition further comprises an effective amount of an opioid.16. A method according to claim 13 , wherein the condition is osteoarthritis and the composition further comprises an effective amount of an opioid.1732.-. (canceled)33. A compound according to wherein said Rand Rare hydrogen.34. A compound according to wherein Ris —OH claim 1 , —CHO claim 1 , —CONH claim 1 , —CON(H)CHCONH claim 1 , —CON(H)CHCHCONH claim 1 , —CON(H)CHCOOH claim 1 , or —CON(H)CHCHCOOH; or Rand Rtogether with the atoms to which they are attached forms a —OCHO— fused ring.35. A compound according to wherein Ris H.37. A compound according to wherein Ris in the para position relative to B and Ris hydrogen or methyl; or Rand Rtogether with the ...

AN IMPROVED PROCESS FOR THE PREPARATION OF BUTORPHANOL TARTRATE

The present invention relates to an improved process for the preparation of Butorphanol tartrate of formula (I), 2. The process as claimed in claim 1 , wherein all the steps or some of the steps is performed in in-situ manner; more particularly the step (a) and (b) claim 1 , the step (c) claim 1 , (d) and (e) and the step (g) and (h) are performed in-situ manner.3. The process as claimed in claim 1 , wherein the said suitable conditions in step (a) comprises condensing of a compound of formula (II) with a compound of formula (III) using an organic solvent under reflux conditions claim 1 , cyclizing using an acid in organic solvent and further reducing with suitable reducing agent in presence of a suitable base.4. The process as claimed in claim 1 , wherein the said solvent used in step (a) and step (b) is preferably selected from the group consisting of water claim 1 ,xylene claim 1 , benzene claim 1 , toluene claim 1 , ethylbenzene claim 1 , cyclohexane or mixture of solvents thereof; more preferably xylene of step (a) and toluene and water mixture of step (b).5. The process as claimed in claim 1 , wherein the said acid used in step (a) is phosphorus oxychloride.6. The process as claimed in claim 3 , wherein the said reducing agent used in step (a) is preferably selected from the group consisting of sodium borohydride claim 3 , lithium borohydride claim 3 , lithium aluminium hydride; more preferably sodium borohydride.7. The process as claimed in claim 1 , wherein the said base of step (a) claim 1 , step (c) and step (f) is preferably selected from organic base or an inorganic base.8. The process as claimed in claim 7 , wherein the said organic base is selected from the group consisting of pyridine or mono claim 7 , di and tri alkyl amine claim 7 , which are further selected from the group consisting of methyl amine claim 7 , triethyl amine claim 7 , diisopropylethyl amine; and the said inorganic base is selected from the group consisting of potassium carbonate ...

HERBICIDAL 3- AZASPIRO[5.5] UNDECANE-8, 10-DIONE COMPOUNDS

The present invention relates to compounds of Formula (I), wherein R, R, R, Rand G are as defined herein. The invention further relates to herbicidal compositions which comprise a compound of Formula (I), to their use for controlling weeds, in particular in crops of useful plants. 2. The compound according to claim 1 , wherein Ris methyl.3. The compound according to claim 1 , wherein Ris methyl.4. The compound according to claim 1 , wherein Ris methoxy.5. The compound according to claim 1 , wherein Ris C-Calkoxy-.6. The compound according to claim 1 , wherein Ris —C(═O)C-Calkyl.7. The compound according to claim 1 , wherein Ris —C(═O)C-Chaloalkyl.8. The compound according to claim 1 , wherein G is hydrogen.9. The compound according to claim 1 , wherein G is —C(O)C-Calkyl.10. The compound according to claim 1 , wherein G is —C(O)—O—C-Calkyl.11. A herbicidal composition comprising a compound of Formula (I) according to and an agriculturally acceptable formulation adjuvant.12. A herbicidal composition according to claim 11 , further comprising at least one additional pesticide.13. A herbicidal composition according to claim 12 , wherein the additional pesticide is an herbicide or herbicide safener.14. A method of controlling weeds at a locus comprising application to the locus of a weed controlling amount of a composition according to .15. Use of a compound of Formula (I) as defined in as a herbicide. The present invention relates to novel herbicidal compounds, to processes for their preparation, to herbicidal compositions which comprise the novel compounds, and to their use for controlling weeds.Herbicidal cyclic dione compounds substituted by a phenyl which has an alkynyl-containing substituent are disclosed in, for example, WO2014/096289 and WO2015/197468. The present invention relates to novel herbicidal cyclohexanedione derivatives with improved properties.Thus, according to the present invention there is provided a compound of Formula (I)Ris selected from the ...

METHODS FOR PREPARING LEVORPHANOL AND RELATED COMPOUNDS, AND COMPOSITIONS THEREOF

A method for producing substantially pure levorphanol and related compounds, when compared to the conventional process, is provided. In particular, a method for producing substantially pure levorphanol tartrate dihydrate is described. Also described are compositions comprising levorphanol and related compounds, particularly compositions comprising levorphanol tartrate dihydrate, levomethorphan, and norlevorphanol in which the levomethorphan and norlevorphanol are present in the composition in reduced levels. 1. A composition comprising levorphanol tartrate dihydrate , levomethorphan , and norlevorphanol , wherein the composition comprises levomethorphan in an amount that is about 0.5% area or less based on peak area of a peak corresponding to levomethorphan as determined by high performance liquid chromatography (HPLC) analysis relative to a total of 100% area based on peak area of peaks corresponding to levorphanol tartrate dihydrate , levomethorphan , and norlevorphanol as determined by HPLC analysis , and norlevorphanol in an amount that is about 0.5% area or less based on peak area of a peak corresponding to norlevorphanol as determined by HPLC analysis relative to a total of 100% area based on peak area of peaks corresponding to levorphanol tartrate dihydrate , levomethorphan , and norlevorphanol as determined by HPLC analysis.2. The composition of claim 1 , comprising levomethorphan in an amount that is about 0.3% area or less based on peak area of the peak corresponding to levomethorphan.3. The composition of claim 2 , comprising levomethorphan in an amount that is about 0.15% area or less based on the peak area of the peak corresponding to levomethorphan.4. The composition of claim 1 , comprising norlevorphanol in an amount that is about 0.3% area or less based on peak area of the peak corresponding to norlevorphanol.5. The composition of claim 4 , comprising norlevorphanol in an amount that is about 0.15% area or less based on the peak area of the peak ...

HERBICIDAL CYCLOHEXANEDIONE DERIVATIVES

The present invention relates to compounds of Formula (I), wherein R, R, R, Rand G are as defined herein. The invention further relates to herbicidal compositions which comprise a compound of Formula (I), to their use for controlling weeds, in particular in crops of useful plants. 2. A compound according to claim 1 , wherein Ris 1-propynyl.3. A compound according to claim 1 , wherein Ris a 5 or 6 membered heteroaryl which comprises one or two nitrogen heteroatoms claim 1 , said phenyl and heteroaryl optionally substituted by one or two Rsubstituents.4. A compound according to claim 1 , wherein Ris chloro.5. A compound according to claim 1 , wherein Ris methoxy.6. A compound according to claim 1 , wherein Ris chloro.7. A compound according to claim 1 , wherein Ris —C(═O)C-Calkyl.8. A compound according to claim 1 , wherein G is hydrogen.9. A compound according to claim 1 , wherein G is —C(O)C-Calkyl.10. A compound according to claim 1 , wherein G is —C(O)—O—C-Calkyl.11. A herbicidal composition comprising a compound of Formula (I) according to and an agriculturally acceptable formulation adjuvant.12. A herbicidal composition according to claim 11 , further comprising at least one additional pesticide.13. A herbicidal composition according to claim 12 , wherein the additional pesticide is a herbicide or herbicide safener.14. A method of controlling weeds at a locus comprising application to the locus of a weed controlling amount of a composition according to .15. Use of a compound of Formula (I) as defined in as a herbicide. The present invention relates to novel herbicidal cyclohexanedione compounds, to processes for their preparation, to herbicidal compositions which comprise the novel compounds, and to their use for controlling weeds.Herbicidal cyclic dione compounds substituted by a phenyl which has various substituents are disclosed in, for example, WO2008/110308. Herbicidal propynyl-phenyl compounds are disclosed in WO2015/197468. The present invention relates ...

COMPOUNDS AND METHODS FOR TREATING CANCER, NEUROLOGICAL DISORDERS, ETHANOL WITHDRAWAL, ANXIETY, DEPRESSION, AND NEUROPATHIC PAIN

Provided herein, inter alia, are compounds and methods of treating diseases including cancer, neurological disease, alcohol withdrawal, depression and anxiety, and neuropathic pain. 2. (canceled)4. The compound of claim 1 , wherein Ris halogen.1. The compound of claim 1 , wherein Ris halogen claim 1 , —CN claim 1 , —C(O)R claim 1 , —OR claim 1 , —NRR claim 1 , —C(O)OR claim 1 , —C(O)NRR claim 1 , —S(O)R claim 1 , —S(O)OR claim 1 , —S(O)NRR claim 1 , —ONRR claim 1 , —NHC(O)NHNRR claim 1 , substituted or unsubstituted alkyl claim 1 , substituted or unsubstituted heteroalkyl claim 1 , substituted or unsubstituted cycloalkyl claim 1 , substituted or unsubstituted heterocycloalkyl claim 1 , substituted or unsubstituted aryl claim 1 , or substituted or unsubstituted heteroaryl.6. (canceled)7. The compound of claim 1 , wherein Ris halogen claim 1 , —NRR claim 1 , substituted or unsubstituted alkyl claim 1 , substituted or unsubstituted heterocycloalkyl claim 1 , substituted or unsubstituted aryl claim 1 , substituted or unsubstituted heteroaryl.8. (canceled)10. The compound of claim 9 , wherein ring A is aryl or heterocycloalkyl.12. The compound of claim 9 , wherein Ris halogen claim 9 , —CF claim 9 , —CN claim 9 , —OH claim 9 , unsubstituted or R-substituted alkyl or unsubstituted or R-substituted heteroalkyl.1317.-. (canceled)18. The compound of claim 1 , wherein Ris —OR claim 1 , —NRR claim 1 , —C(O)OR claim 1 , substituted or unsubstituted alkyl claim 1 , substituted or unsubstituted cycloalkyl claim 1 , substituted or unsubstituted heterocycloalkyl claim 1 , substituted or unsubstituted aryl claim 1 , substituted or unsubstituted heteroaryl.19. (canceled)20. The compound of claim 1 , wherein Ris —C(O)OR claim 1 , wherein Ris R-substituted or unsubstituted aryl claim 1 , wherein Ris —CF claim 1 , —CN claim 1 , —OH claim 1 , unsubstituted alkyl or R-substituted or unsubstituted heteroalkyl.21. (canceled)22. The compound of claim 1 , wherein Ris R-substituted or ...

BENZOMORPHAN COMPOUNDS AS OPIOID RECEPTORS MODULATORS

The present invention is directed to Benzomorphan Analog compounds of the Formula (I), Formula (IA), Formula (IB), Formula (IC), or Formula (ID) as shown below, wherein R, R, R, R, R, Z, and G are as defined herein. Compounds of the Invention are useful for treating pain, constipation, and other conditions modulated by activity of opioid and ORL-1 receptors. 14-. (canceled)69-. (canceled)10. The compound of claim 5 , wherein Z is methylene.11. The compound of claim 5 , wherein Z is ethylene.12. The compound of claim 5 , wherein Z is propylene.1314-. (canceled)15. The compound of claim 5 , wherein G is (C-C)alkylene.16. (canceled)17. The compound of claim 5 , wherein G is (C-C)alkenylene.18. The compound of claim 17 , wherein G ethenylene.19. The compound of claim 5 , wherein G is —C(═O)—.20. The compound of claim 5 , wherein G is —O—.214. The compound of claim claim 5 , wherein G is —NR—.2223-. (canceled)24. The compound of claim 5 , wherein Ris NHor NH(C-C)alkyl.25. The compound of claim 5 , wherein Ris selected from the group consisting of —CONRRand (C-C)alkyl-CONRR.2627-. (canceled)28. The compound of claim 5 , wherein Ris COOR.2930-. (canceled)31. The compound of claim 5 , wherein Ris phenyl or benzyl.32. The compound of claim 5 , wherein Ris —C(═O)-(6- to 14-membered)aryl or —C(═O)-(5- to 12-membered)heteroaryl.3335-. (canceled)36. The compound of claim 5 , wherein Ris substituted with one claim 5 , two or three substituents independently selected from the group consisting of —COOR claim 5 , —NRR claim 5 , —CONRR claim 5 , phenyl claim 5 , benzyl claim 5 , —NH—C(═O)-(6- to 14-membered)aryl claim 5 , with —NH—C(═O)—(C-C)alkyl-(6- to 14-membered)aryl claim 5 , —OH claim 5 , hydroxy(C-C)alkyl- claim 5 , and dihydroxy(C-C)alkyl.3739-. (canceled)40. The compound of claim 5 , wherein Ris cyclopropylmethyl-.41. (canceled)42. The compound of claim 5 , wherein Ris —OH or —OCH.4367-. (canceled)70. A pharmaceutical composition comprising an effective amount of a compound ...

MORPHINAN DERIVATIVES FOR THE TREATMENT OF NEUROPATHIC PAIN

The present invention relates to compounds and their use as ligands for mu opioid receptors. Also included are methods for preparing the compounds and pharmaceutical compositions containing the compounds. In one or more embodiments of the invention, a compound according to Formula I is provided: and pharmaceutically acceptable salts thereof, wherein R-Rare as described herein. 2. The compound of claim 1 , wherein Ris hydrogen.3. The compound of or claim 1 , wherein Ris hydrogen.4. The compound of any one of to claim 1 , wherein Ris hydrogen.5. The compound of any one of to claim 1 , wherein Ris hydrogen.6. The compound of any one of to claim 1 , wherein Ris lower alkyl.7. The compound of any one of to claim 1 , wherein Ris methyl.8. The compound of any one of to claim 1 , wherein Ris hydrogen.9. The compound of any one of to claim 1 , wherein Ris hydrogen.10. The compound of any one of to claim 1 , wherein Rand Rare hydrogen.11. The compound of any one of to claim 1 , wherein Rand Rtogether from a carbonyl.12. The compound of any one of to claim 1 , wherein Ris hydrogen.13. The compound of any one of to claim 1 , wherein Ris selected from:{'sup': 13', '14', '15', '16', '17', '18', '19', '20', '21', '22, 'sub': 2', '2', '2', 'n, '—O—C(O)—N(R)(R), —NHC(O)—(R), —NH—C(O)—NH(R), —N(R)(R), —NHC(O)O—(R), —NH—S(O)—(R), —C(O)—N(R)(R), optionally substituted heterocyclyl, optionally substituted heteroaryl, and —X—(CHCHO)—R, where n is 1 to 30 and R is selected from hydrogen, lower alkyl, haloalkyl, and carboxyl.'}15. The compound of any one of the preceding claims claim 1 , wherein Ris selected from:{'sup': 13', '14', '13', '14, '—O—C(O)—N(R)(R) wherein Ris selected from hydrogen and optionally substituted lower alkyl and Ris selected from hydrogen and optionally substituted lower alkyl;'}{'sup': 15', '15, '—NHC(O)—(R) wherein Ris selected from hydrogen, optionally substituted phenyl, and optionally substituted lower alkyl;'}{'sup': 16', '16, 'sub': 2', '2', 'n, '—NH—C(O)—NH( ...

2-SPIRO-5- AND 6-HYDROXAMIC ACID INDANES AS HDAC INHIBITORS

The present invention is directed to inhibitors of histone deacetylases (HDACs) such as HDAC6, and their use in the treatment of diseases such as cell proliferative diseases (e.g., cancer), neurological (e.g., neurodegenerative disease or neurodevelopmental disease), inflammatory or autoimmune disease, infection, metabolic disease, hematologic disease, or cardiovascular disease. 231-. (canceled)32. The compound of claim 1 , wherein n is 0.33. The compound of claim 1 , wherein n is 1.34. The compound of claim 1 , wherein Xis —CH— and Xis —CH—.35. The compound of claim 1 , wherein Xis —C(O)—.36. The compound of claim 34 , wherein Yand Yare each CR claim 34 , wherein —C(O)NHOH is attached at Yor Y claim 34 , and Yor Yis a carbon atom when attached to —C(O)NHOH.37. The compound of claim 36 , wherein L is a bond claim 36 , —(CRR)— claim 36 , or —C(O)(CRR)—.38. The compound of claim 37 , wherein p is 0 or 1.39. The compound of claim 38 , wherein R is —H or an optionally substituted group selected from —C-Calkyl claim 38 , aryl claim 38 , and heteroaryl.40. The compound of claim 39 , wherein R is an optionally substituted group selected from aryl or heteroaryl.44. A compound of selected from:(R)-N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide (I-32);(S)-N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide (I-33);(R)-1′-benzyl-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide (I-34);(S)-1′-benzyl-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide (I-35);(R)-N-hydroxy-2′-oxo-1′-phenyl-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide (I-36);(S)-N-hydroxy-2′-oxo-1′-phenyl-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide (I-37);N-hydroxy-1′-methyl-6′-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-5-carboxamide (I-39);N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-5-carboxamide (I-40);N-hydroxy-1′-methyl-1,3-dihydrospiro[indene-2,3′-piperidine ...

N-[3-(2-CARBOXYETHYL)PHENYL]PIPERIDIN-1-YLACETAMIDE DERIVATIVES AND USE THEREOF AS ACTIVATORS OF SOLUBLE GUANYLATE CYCLASE

The present application relates to novel substituted 2-(piperidin-1-yl)acetamide derivatives, to processes for preparation thereof, to the use thereof for treatment and/or prevention of diseases, and to the use thereof for production of medicaments for treatment and/or prevention of diseases, especially for treatment and/or prevention of cardiovascular diseases. 5. Compound as defined in for treatment and/or prevention of diseases.6. Use of a compound as defined in for production of a medicament for treatment and/or prevention of heart failure claim 1 , angina pectoris claim 1 , hypertension claim 1 , pulmonary hypertension claim 1 , thromboembolic disorders claim 1 , ischaemias claim 1 , vascular disorders claim 1 , impaired microcirculation claim 1 , renal insufficiency claim 1 , fibrotic disorders and arteriosclerosis.7. Medicament comprising a compound as defined in in combination with one or more inert claim 1 , nontoxic claim 1 , pharmaceutically suitable excipients.8. Medicament comprising a compound as defined in in combination with one or more further active compounds selected from the group consisting of organic nitrates claim 1 , NO donors claim 1 , cGMP-PDE inhibitors claim 1 , stimulators of guanylate cyclase claim 1 , antithrombotic agents claim 1 , hypotensive agents and lipid metabolism modifiers.9. Medicament according to for the treatment and/or prevention of heart failure claim 7 , angina pectoris claim 7 , hypertension claim 7 , pulmonary hypertension claim 7 , thromboembolic disorders claim 7 , ischaemias claim 7 , vascular disorders claim 7 , impaired microcirculation claim 7 , renal insufficiency claim 7 , fibrotic disorders and arteriosclerosis.10. Method for treatment and/or prevention of heart failure claim 1 , angina pectoris claim 1 , hypertension claim 1 , pulmonary hypertension claim 1 , thromboembolic disorders claim 1 , ischaemias claim 1 , vascular disorders claim 1 , impaired microcirculation claim 1 , renal insufficiency claim 1 , ...

RADICAL COMPOUNDS AND METHODS OF USING THEREOF

Disclosed are methods for performing dynamic nuclear polarization using the polarizing agents described herein. In general, the methods involve (a) providing a frozen sample in a magnetic field, wherein the frozen sample includes a polarizing agent described herein and an analyte with at least one spin half nucleus; (b) polarizing the at least one spin half nucleus of the analyte by irradiating the frozen sample with radiation having a frequency that excites electron spin transitions in the polarizing agent; (c) optionally melting the sample to produce a molten sample; and (d) detecting nuclear spin transitions in the at least one spin half nucleus of the analyte in the frozen or molten sample. In certain embodiments, the polarizing agents can be peptide-based. In these embodiments, the polarizing agents can be readily prepared by solid-phase peptide synthesis. 5. The compound of claim 1 , wherein L represents a direct bond.6. The compound of claim 1 , wherein L comprises one or more amino acid residues.8. The compound of claim 7 , wherein m is 1.9. The compound of claim 7 , wherein m is 2.10. The compound of claim 6 , wherein L comprises a serine residue claim 6 , a threonine residue claim 6 , or any combination thereof.11. The compound of claim 6 , wherein L comprises a 2 claim 6 ,2 claim 6 ,6 claim 6 ,6-tetramethyl-N-oxyl-4-amino-4-carboxylic acid residue.12. The compound of claim 6 , wherein L comprises an asparagine residue.13. The compound of claim 6 , wherein L comprises a glutamine residue.14. The compound of claim 6 , wherein L comprises an aspartic acid residue claim 6 , a glutamic acid residue claim 6 , or any combination thereof.15. The compound of claim 6 , wherein L comprises a cysteine residue16. The compound of claim 1 , wherein L comprises from 3 to 20 atoms.17. The compound of claim 1 , wherein Ris H.18. The compound of claim 1 , wherein Rcomprises an amino acid residue.19. The compound of claim 18 , wherein the amino acid residue is selected from ...

(--)-Huperzine A Processes and Related Compositions and Methods of Treatment

The invention provides (1) processes for making substantially-pure (−) huperzine A and substantially-pure (−) huperzine A derivatives; (2) compositions useful in making substantially-pure (−) huperzine A and substantially-pure (−) huperzine A derivatives; and (3) methods of treating or preventing neurological disorders using substantially-pure (−) huperzine A and substantially-pure (−) huperzine A derivatives. 2. The process of claim 1 , wherein the alcohol solvent is methanol and the (−) huperzine A is further purified by crystallization or flash column chromatography.3. The process of claim 1 , wherein the substantially pure (−) huperzine A contains less than about one percent by weight of (+) huperzine A.5. (canceled)7. (canceled)9. The process of claim 8 , wherein the addition alkylation product is reacted in a solvent selected from the group consisting of THF or toluene claim 8 , the palladium-catalyzed intramolecular enolate heteroarylation base is sodium tert-butoxide claim 8 , the Wittig olefination reaction base is selected from the group consisting of n-butyllithium claim 8 , sodium bis(trimethylsilyl)amide claim 8 , lithium bis(trimethylsilyl)amide claim 8 , potassium bis(trimethylsilyl)amide or lithium diisopropylamide claim 8 , and the Wittig olefination reaction organic solvent is selected from the group consisting of THF claim 8 , diethylether or 1 claim 8 ,4-dioxane.12. The process of claim 11 , wherein:(a) the the addition alkylation product is reacted with lithium bis(trimethylsilyl) amide (LHMDS) or lithium diisopropyl amide (LDA) in THF or toluene;(b) the palladium-catalyzed intramolecular enolate heteroarylation base is sodium tert-butoxide;(c) the Wittig olefination reaction base is selected from the group consisting of n-butyllithium, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide and lithium diisopropylamide; and the Wittig olefination reaction organic solvent is selected from the group ...

PREPARATION OF (-)-HUPERZINE A

The present invention relates to a method for preparing (−)-huperzine A. The method involves: allowing a mixture of (±)-huperzine A obtained from chemical synthesis and a chiral acid to form (±)-huperzine A chiral acid salt under suitable conditions; recrystallizing the chiral acid salt from an organic solvent and basifying with an alkali to obtain optically pure (−)-huperzine A. The method is convenient to operate and suitable for industrial production. The chemical purity and optical purity of (−)-huperzine A obtained by the method are each greater than 99.5%, satisfying the requirement for raw pharmaceutical purity in the pharmaceutical industry. 1. A method of synthesizing (−)-huperzine A , said method comprising the following steps:1) Forming a salt between (±)-huperzine A and a chiral acid to give (−)-huperzine A-chiral acid salt; and2) Basifying the (−)-huperzine A-chiral acid salt to give (−) huperzine A;wherein said chiral acid in step 1) is selected from D-dibenzoyl tartaric acid, D-tartaric acid, D-malic acid, D-mandelic acid and D-camphor sulfonic acid; wherein said salt in step 1) is formed by reaction of (±)-huperzine A with said chiral acid in a solvent, wherein said solvent is selected from acetone-water and ethanol-water.2. The method of claim 1 , wherein said chiral acid in step 1) is D-dibenzoyl tartaric acid;wherein the solvent used in step 1) is selected from acetone-water and ethanol-water, wherein the ratio of acetone-water is 1:1 to 5:1; wherein the ratio of ethanol-water is 1:1 to 5:1; wherein the molar ratio of (±)-huperzine A to chiral acid ranges from 1:0.5 to 1:2.3. The method of claim 2 , wherein the ratio of acetone-water is 1:1 to 3:1; wherein the ratio of ethanol-water is 1:1 to 3:1; wherein the molar ratio of (±)-huperzine A to chiral acid ranges from 1:0.75 to 1:1.5.4. The method of claim 3 , wherein the ratio of acetone-water is 1:1; wherein the ratio of ethanol-water is 1:1; wherein the molar ratio of (±)-huperzine A to chiral ...

Aromatic compound and organic electroluminescence device including the same

Provided are an aromatic compound enhancing emission efficiency of blue light emitting region and an organic electroluminescence device including the same. The aromatic compound according to an embodiment of the inventive concept is represented by Formula 1, and more details about the constituents are provided in the disclosure.

2-SPIRO-5- AND 6-HYDROXAMIC ACID INDANES AS HDAC INHIBITORS

The present invention is directed to inhibitors of histone deacetylases (HDACs) such as HDAC6, and their use in the treatment of diseases such as cell proliferative diseases (e.g., cancer), neurological (e.g., neurodegenerative disease or neurodevelopmental disease), inflammatory or autoimmune disease, infection, metabolic disease, hematologic disease, or cardiovascular disease. 240-. (canceled)41. The compound of claim 1 , wherein n is 1 claim 1 , and m is 2.42. The compound of claim 1 , wherein n is 2.43. The compound of claim 42 , wherein m is 1.44. The compound of claim 42 , wherein m is 2.45. The compound of claim 1 , wherein n is 3.46. The compound of claim 45 , wherein m is 0.47. The compound of claim 45 , wherein m is 1.48. The compound of claim 1 , wherein n is 4 claim 1 , and m is 0.49. The compound of claim 1 , wherein Xis —CH—and Xis —CH—.50. The compound of claim 1 , wherein Xis C(O).51. The compound of claim 49 , wherein Yand Yare each CR claim 49 , wherein —C(O)NHOH is attached at Yor Y claim 49 , and Yor Yis a carbon atom when attached to C(O)NHOH.52. The compound of claim 51 , wherein L is a bond claim 51 , —(CRR)— claim 51 , or —C(O)(CRR)—.53. The compound of claim 52 , wherein p is 0 or 1.54. The compound of claim 53 , wherein R is —H or an optionally substituted group selected from —C-Calkyl claim 53 , aryl claim 53 , and heteroaryl.55. The compound of claim 54 , wherein R is an optionally substituted group selected from aryl or heteroaryl.58. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier. This application is a divisional of U.S. application Ser. No. 16/719,332, filed Dec. 18, 2019, which is a divisional of U.S. application No. 16/309,980, filed Dec. 14, 2018, which is a national stage entry of PCT/US17/37970, filed Jun. 16, 2017, which claims the benefit of and priority to U.S. provisional application No. 62/351,399, filed Jun. 17, 2016, the entire contents of each of which are incorporated ...

6-substituted and 7-substituted morphinan analogs and the use thereof

The application is directed to compounds of Formula I or II: and pharmaceutically acceptable salts and solvates thereof, wherein R′, R″, R′″ R 1 , R 2 , R 3 , R 4 , R 4a , and R 20 are defined as set forth in the specification. The invention is also directed to use of compounds of Formula I or II and the pharmaceutically acceptable salts and solvates thereof to treat disorders responsive to the modulation of one or more opioid receptors. Certain compounds of the invention are especially useful for treating pain.

8-CARBOXAMIDO-2,6-METHANO-3-BENZAZOCINES

8-Substituted-2,6-methano-3-benzazocines of general structure I in which A is —CH—OH, —CHNH, —NHSOCH, 2. A compound according to wherein A is chosen from the group consisting of: —COOCH claim 1 , —COOEt claim 1 , —CONH claim 1 , —C(═S)NH claim 1 , —C(O)NHOH claim 1 , —C(O)NHNH claim 1 , —CONHCH claim 1 , —CONHBn claim 1 , —CONHCH(4-MeOCH) claim 1 , C(═NOH)NH claim 1 , C(═NOH)CH claim 1 , —NHCHO and —NHCHS.5. The method according to wherein A is chosen from the group consisting of: —COOCH claim 4 , —COOEt claim 4 , —CONH claim 4 , —C(═S)NH claim 4 , —C(O)NHOH claim 4 , —C(O)NHNH claim 4 , —CONHCH claim 4 , —CONHBn claim 4 , —CONHCH(4-MeOCH) claim 4 , —C(═NOH)NH claim 4 , -C(=NOH)CH claim 4 , —NHCHO and -NHCHS. This application is a continuation of copending U.S. application Ser. No. 13/556,650, filed Jul. 24, 2012, now allowed, which was a divisional of U.S. application Ser. No. 13/103,599, filed May 9, 2011, now U.S. Pat. No. 8,252,929, which was a continuation of U.S. application Ser. No. 12/249,238, filed Oct. 10, 2008, now U.S. Pat. No. 7,956,187, which was a divisional of U.S. application Ser. No. 11/205,354, filed Aug. 17, 2005, now abandoned, which was a divisional of U.S. application Ser. No. 10/987,527, filed Nov. 12, 2004, now U.S. Pat. No. 7,265,226, which was a divisional of U.S. application Ser. No. 10/409,803, filed Apr. 9, 2003, now U.S. Pat. No. 6,887,998, which was a divisional of Ser. No. 10/305,287, filed Nov. 26, 2002, now U.S. Pat. No. 6,784,187. U.S. Ser. No. 10/305,287 was a continuation-in-part of PCT International Application PCT/US01/045581, filed Oct. 31, 2001, and published under PCT Article 21(2) in English as WO 02/36573 on May 10, 2002. PCT/US01/045581 claimed benefit from United States Provisional Application 60/244,438, filed Oct. 31, 2000. The entire contents of each of the prior applications are incorporated herein by reference.This invention was made with Government support under Contract No. R01 DA12180, awarded by the National ...

AZEPANE DERIVATIVES AND METHODS OF TREATING HEPATITIS B INFECTIONS

Provided herein are compounds useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject. 3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein each Ris claim 2 , independently at each occurrence claim 2 , halo.4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein each Ris claim 2 , independently at each occurrence claim 2 , halo or —C-Calkyl claim 2 , wherein the alkyl is optionally substituted 1-3 times with halo.7. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , together with a pharmaceutically acceptable carrier.8. A method of treating an HBV infection in an individual in need thereof claim 1 , comprising administering to the individual a therapeutically effective amount of a compound of .9. A method of reducing the viral load associated with an HBV infection in an individual in need thereof claim 1 , comprising administering to the individual a therapeutically effective amount of a compound of .10. A method of reducing reoccurrence of an HBV infection in an individual in need thereof claim 1 , comprising administering to the individual a therapeutically effective amount of a compound of .11. A method of inducing remission of hepatic injury from an HBV infection in an individual in need thereof claim 1 , comprising administering to the individual a therapeutically effective amount of a compound of .12. The method of claim 8 , further comprising administering to the individual at least one additional therapeutic agent selected from the group consisting of a HBV polymerase inhibitor claim 8 , immunomodulatory agents claim 8 , pegylated interferon claim 8 , viral entry inhibitor claim 8 , viral maturation inhibitor claim 8 , literature-described capsid assembly modulator claim 8 , ...

BENZOMORPHAN COMPOUNDS AS OPIOID RECEPTORS MODULATORS

The present invention is directed to Benzomorphan Analog compounds of the Formula (I), Formula (IA), Formula (IB), Formula (IC), or Formula (ID) as shown below, wherein R, R, R, R, R, Z, and G are as defined herein. Compounds of the Invention are useful for treating pain, constipation, and other conditions modulated by activity of opioid and ORL-1 receptors. 9. A compound of any one of to , wherein Z is absent.10. A compound of any one of to , wherein Z is methylene.11. A compound of any on of to , wherein Z is ethylene.12. A compound of any one of to , wherein Z is propylene.13. A compound of any one of to , wherein Z is butylene.1413. A compound of any one of claims 1 , wherein G is a bond.15. A compound of any one of to claims 1 , wherein G is —(C-C)alkylene.16. A compound of claim 15 , wherein G is selected from the group consisting of methylene claim 15 , ethylene claim 15 , and propylene.17. A compound of any one of to claim 15 , wherein G is —(C-C)alkenylene.18. A compound of claim 17 , wherein G is selected from the group consisting of ethenylene and propenylene.19. A compound of any one of to claim 17 , wherein G is —C(═O).20. A compound of any one of to claim 17 , wherein G is —O.21. A compound of any one of to claim 17 , wherein G is NR.22. A compound of claim 21 , wherein Ris selected from the group consisting of —H claim 21 , —(C-C)alkyl claim 21 , —(C-C)alkoxy claim 21 , —(C-C)cycloalkyl claim 21 , and ((C-C)cycloalkyl)-(C-C)alkyl-.23. A compound of any one of to claim 21 , wherein Ris H or (C-C)alkyl.24. A compound of any one of to claim 21 , wherein Ris NHor NH(C-C)alkyl.25. A compound of any one of to claim 21 , wherein Ris selected from the group consisting of —CONRRand —(C-C)alkyl-CONRR.26. A compound of claim 25 , wherein Ror Rare each independently selected from —H or —(C-C)alkyl.27. A compound of any one of to claim 25 , wherein Ris selected from the group consisting of —C(═O) and —C(═O)—(C-C)alkyl.28. A compound of any one of to claim 25 , ...

1,1,1-TRIFLUORO-3-HYDROXYPROPAN-2-YL CARBAMATE DERIVATIVES AS MAGL INHIBITORS

The present invention provides, in part, compounds of Formula I: 2. The compound of or a pharmaceutically acceptable salt thereof claim 1 , wherein each Ris independently selected from the group consisting of halogen claim 1 , Calkyl claim 1 , Chaloalkyl claim 1 , Calkoxy claim 1 , and Chaloalkoxy.3. The compound of or a pharmaceutically acceptable salt thereof claim 2 , wherein n1 is 0.4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof claim 3 , wherein each Ris independently Calkyl; and each Ris independently selected from Calkyl claim 3 , Ccycloalkyl claim 3 , (Ccycloalkyl)-Calkyl- claim 3 , (Caryl)-Calkyl- claim 3 , (5- or 10-membered heteroaryl)-Calkyl- claim 3 , 5- or 10-membered heteroaryl claim 3 , and Caryl claim 3 , wherein each of the selections is substituted with 0 claim 3 , 1 claim 3 , 2 claim 3 , or 3 halogen.5. The compound of claim 3 , or a pharmaceutically acceptable salt thereof claim 3 , wherein each Ris independently Calkyl; and each Ris independently selected from Calkyl claim 3 , Ccycloalkyl claim 3 , (Ccycloalkyl)-Calkyl- claim 3 , (Caryl)-Calkyl- claim 3 , and Caryl claim 3 , wherein each of the selections is substituted with 0 claim 3 , 1 claim 3 , 2 claim 3 , or 3 halogen.7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof claim 6 , wherein Ris H or —P(═O)(OH)(OH).8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof claim 7 , wherein Ris H.9. The compound of claim 6 , or a pharmaceutically acceptable salt thereof claim 6 , wherein the compound is a compound of Formula 1-1.10. The compound of claim 6 , or a pharmaceutically acceptable salt thereof claim 6 , wherein Ris Ror —OR.11. The compound of claim 6 , or a pharmaceutically acceptable salt thereof claim 6 , wherein Ris R; and Ris selected from the group consisting of phenyl claim 6 , 1H-pyrazolyl claim 6 , and pyridinyl claim 6 , wherein each of the selections is substituted with 0 claim 6 , 1 claim 6 , 2 claim 6 , or ...

HETEROCYCLIC COMPOUNDS

The invention concerns heterocyclic compounds and electronic devices, in particular organic electroluminescent devices, containing these compounds. 121.-. (canceled)23. The compound of claim 22 , wherein the heteroaromatic ring system having the Xradical is a system having 10 to 30 aromatic ring atoms.25. The compound of claim 22 , wherein Q is the same or different at each instance and is X═X.26. The compound of claim 22 , wherein claim 22 , in the ring structures of one of the formulae (5) claim 22 , (6) claim 22 , (7) claim 22 , (8) claim 22 , (9) claim 22 , (10) and/or (11) claim 22 , not more than two of the A claim 22 , Aand Agroups is O claim 22 , S or NR.27. The compound of claim 22 , wherein claim 22 , in the ring structures of one of the formulae (5) claim 22 , (6) claim 22 , (7) claim 22 , (8) claim 22 , (9) claim 22 , (10) and/or (11) claim 22 , at least one of the Aand Agroups is the same or different and is O or NRand Ais C(R).28. The compound of claim 22 , wherein claim 22 , in the ring structures of one of the formulae (5) claim 22 , (6) claim 22 , (7) claim 22 , (8) claim 22 , (9) claim 22 , (10) and/or (11) claim 22 , the Aand Agroups are the same or different at each instance and are C(R)and Ais C(R).29. The compound of claim 22 , wherein claim 22 , in the ring structures of formulae (8) claim 22 , (9) claim 22 , (10) and/or (11) claim 22 , the Rradicals bonded to the bridgehead are H claim 22 , D claim 22 , F or CH.34. The compound of claim 22 , wherein the compound has at least two ring structures of the formulae (5) to (11).36. An oligomer claim 22 , polymer or dendrimer containing one or more compounds as claimed in claim 22 , wherein one or more bonds of the compound to the polymer claim 22 , oligomer or dendrimer are present.37. A composition comprising at least one compound as claimed in and at least one additional organic functional material.38. A formulation comprising at least one compound as claimed in and at least one solvent.39. A ...

METHODS OF RESOLVING RACEMIC MIXTURE TO OBTAIN (-)-HUPERZINE A

A method of resolving a racemic mixture of (±)-Huperzine A to (−)-Huperzine A includes: separating the (−)-Huperzine A from the racemic mixture of (±)-Huperzine A by chiral high performance liquid chromatography (HPLC), the chiral HPLC being performed utilizing a mobile phase including a solution including an alcohol and one selected from dichloromethane, trichloromethane, and a mixture thereof, and the chiral HPLC being performed utilizing a chiral stationary phase including a polysaccharide derivative. 1. A method of resolving a racemic mixture of (±)-Huperzine A to (−)-Huperzine A , the method comprising:separating the (−)-Huperzine A from the racemic mixture of (±)-Huperzine A by chiral high performance liquid chromatography (HPLC),the chiral HPLC being performed utilizing a mobile phase comprising a solution comprising an alcohol comprising methanol, dichloromethane, and an organic base comprising diethylamine, andthe chiral HPLC being performed utilizing a chiral stationary phase comprising a polysaccharide derivative,wherein the enantiomeric excess of the resultant (−)-Huperzine A is 99.0% or more, the enantiomeric excess being calculated by dividing the peak area of the (−)-Huperzine A by the total peak area of the (−)-Huperzine A and the (+)-Huperzine A.2. The method of claim 1 , wherein the alcohol further comprises ethanol claim 1 , isopropanol claim 1 , or a mixture thereof.3. The method of claim 1 , wherein a volume ratio of a volume of the dichloromethane to a volume of the alcohol is 8:1 to 1:8.4. The method of claim 3 , wherein the volume ratio of the volume of the dichloromethane to the volume of the alcohol is 4:1 to 1:4.5. The method of claim 4 , wherein the volume ratio of the volume of the dichloromethane to the volume of the alcohol is 2:8 to 5:8.6. The method of claim 1 , wherein the mobile phase comprises the organic base at a concentration of less than 5 vol % based on the total volume of the mobile phase.7. The method of claim 6 , wherein ...

Morphan And Morphinan Analogues, And Methods Of Use

The present application relates to analogues of morphan and morphinan, compositions thereof, and methods for treating a disease or condition comprising administering an effective amount of the compounds or compositions to a subject in need thereof. 19-. (canceled)1120-. (canceled)21. The compound of claim 10 , wherein the compound is a μ opioid receptor agonist having an Emax of 5% to 45% in a GTPγS binding assay.2229-. (canceled)30. A method of treating a depressive symptom in a subject in need thereof claim 10 , the method comprising administering to the subject an effective amount of a compound of .3132-. (canceled)33. A method of treating a depressive symptom in a subject in need thereof claim 21 , the method comprising administering to the subject an effective amount of a compound of .3440-. (canceled)41. The method of claim 30 , wherein the depressive symptom is acute stress disorder claim 30 , adjustment disorders with depressed mood claim 30 , Asperger syndrome claim 30 , attention deficit claim 30 , bereavement claim 30 , bipolar I disorder claim 30 , bipolar II disorder claim 30 , borderline and personality disorder claim 30 , cyclothymia and dysthymia claim 30 , depression such as major depressive disorder (MDD) and treatment-resistant disorder (TRD) claim 30 , Dysthymic disorder claim 30 , hyperactivity disorder claim 30 , impulse control disorder claim 30 , mixed mania claim 30 , obsessive-compulsive personality disorder (OCD) claim 30 , paranoid claim 30 , post-traumatic stress disorder claim 30 , seasonal affective disorder claim 30 , self-injury separation claim 30 , sleep disorder claim 30 , substance-induced mood disorder claim 30 , Tourette syndrome and tic disorder claim 30 , and/or Trichotillomania.4243-. (canceled)44. A method of treating a disease or condition associated with the group consisting of pain claim 10 , pruritis claim 10 , diarrhea claim 10 , irritable bowel syndrome claim 10 , gastrointestinal motility disorder claim 10 , obesity ...

Morphinan Compounds

This disclosure relates to novel morphinan compounds and their derivatives, pharmaceutically acceptable salts, solvates, and hydrates thereof. This disclosure also provides compositions comprising a compound of this disclosure and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a σreceptor agonist that also has NMDA antagonist activity. 111.-. (canceled)13. The method of claim 12 , wherein Ris CD claim 12 , and Ris selected from CH claim 12 , CHD claim 12 , CHD claim 12 , and CD.14. The method of claim 13 , wherein Ris CD claim 13 , and Ris CD.15. The method of claim 13 , wherein Ris CD claim 13 , and Ris CH.16. The method of claim 12 , wherein Ris CH claim 12 , and Ris CH.17. The method of claim 12 , further comprising administering to the subject a pharmaceutically acceptable carrier.18. The method of claim 12 , wherein the pharmaceutically acceptable salt is the HBr salt.19. The method of claim 12 , further comprising administering to the subject in need thereof a second therapeutic agent selected from quinidine or a salt thereof claim 12 , oxycodone claim 12 , and gabapentin.20. The method of claim 19 , wherein Ris CD claim 19 , and Ris selected from CH claim 19 , CHD claim 19 , CHD claim 19 , and CD.21. The method of claim 20 , wherein Ris CD claim 20 , and Ris CD.22. The method of claim 20 , wherein Ris CD claim 20 , and Ris CH.23. The method of claim 19 , wherein Ris CH claim 19 , and Ris CH.24. The method of claim 19 , wherein the second therapeutic agent is quinidine or quinidine sulfate.26. The method of claim 25 , further comprising administering to the subject a pharmaceutically acceptable carrier.27. The method of claim 25 , wherein the pharmaceutically acceptable salt is the HBr salt.28. The method of claim 25 , further comprising administering to the subject in need thereof a second therapeutic agent selected from quinidine or a salt thereof claim 25 , oxycodone claim 25 , and ...

(--)-HUPERZINE A PROCESSES AND RELATED COMPOSITIONS AND METHODS OF TREATMENT

The invention provides (1) processes for making substantially-pure (−) huperzine A and substantially-pure (−) huperzine A derivatives; (2) compositions useful in making substantially-pure (−) huperzine A and substantially-pure (−) huperzine A derivatives; and (3) methods of treating or preventing neurological disorders using substantially-pure (−) huperzine A and substantially-pure (−) huperzine A derivatives. 1. (canceled)2. (canceled)3. (canceled)4. (canceled)5. (canceled)6. (canceled)7. (canceled)8. (canceled)9. (canceled)10. (canceled)11. (canceled)12. (canceled)17. (canceled)18. (canceled)19. (canceled)20. (canceled)21. (canceled)22. (canceled)23. (canceled)24. (canceled)25. (canceled)26. (canceled)27. (canceled)28. (canceled)29. (canceled)30. (canceled)31. (canceled)32. (canceled)33. (canceled)34. (canceled)35. (canceled)38. (canceled)39. (canceled)40. (canceled)41. (canceled)42. (canceled)43. (canceled)44. (canceled) This application claims the benefit of priority of U.S. Provisional Application Ser. No. 61/449,198, entitled “Huperzine A”, filed Mar. 4, 2011, the entire contents of which are incorporated by reference herein.(−)-Huperzine A (1) is a tricyclic alkaloid produced by the Chinese herb (−)-Huperzine A (1) is a potent, selective, and reversible inhibitor of acetylcholine esterase (AChE, Ki=23 nM).Recent studies have established that this activity may be exploited to counteract organophosphate chemical warfare agents, such as sarin and VX, by inhibiting their covalent modification of peripheral and cerebral AChE.A large body of evidence also suggests that (−)-huperzine A (1) may slow the progression of neurodegenerative diseases, including Alzheimer's disease.(−)-Huperzine A (1) is well tolerated in humans, even at doses well above those required clinically.Consequently, clinical investigation of (−)-huperzine A (1) is a subject of intense research in the pharmaceutical and defense industries.The primary obstacle to the clinical development of (−)- ...

INHIBITORS OF HIF PROLYL HYDROXYLASE

The present invention concerns a compound of formula I or a pharmaceutically acceptable salt thereof, which inhibit HIF prolyl hydroxylase, their use for enhancing endogenous production of erythropoietin, and for treating conditions associated with reduced endogenous production of erythropoietin such as anemia and like conditions, as well as pharmaceutical compositions comprising such a compound and a pharmaceutical carrier. 3. A compound which is:2-(4-Hydroxy-2-oxo-1-(4-(trifluoromethyl)benzyl)-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;2-(4-Hydroxy-2-oxo-1-(4-(trifluoromethyl)benzyl)-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;2-(4-Hydroxy-7-methyl-2,6-dioxo-1-(4-(trifluoromethyl)benzyl)-1,2,5,6,7,8-hexahydro-1,7-naphthyridine-3-carboxamido)acetic acid;2-(4-Hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;2-(1-(4-Cyanobenzyl)-4-hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;2-(4-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;2-(4-hydroxy-2-oxo-1-(4-(trifluoromethoxy)benzyl)-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;2-(1-(4-(difluoromethoxy)benzyl)-4-hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;2-(1-(4-fluorobenzyl)-4-hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;2-(1-(4-chlorobenzyl)-4-hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;2-(4-hydroxy-1-(4-(methylsulfonyl)benzyl)-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;2-(4-hydroxy-1-(4-isopropylbenzyl)-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;2-(4-hydroxy-1-(4-isopropoxybenzyl)-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;2-(1-(benzo[d]thiazol-2-ylmethyl)-4-hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4, ...

METHODS FOR THE SYNTHESIS OF DEUTERATED DEXTROMETHORPHAN

The application describes methods for making a deuterated dextromethorphan of Formula (I), deuterated dextromethorphan produced by these methods, and pharmaceutically acceptable salts thereof. 2. The method of claim 1 , wherein the base used in step (i) is chosen from sodium carbonate claim 1 , cesium carbonate claim 1 , potassium carbonate claim 1 , sodium bicarbonate claim 1 , potassium bicarbonate claim 1 , sodium hydroxide claim 1 , potassium hydroxide claim 1 , potassium tert-butoxide claim 1 , sodium hydride claim 1 , n-butyllithium claim 1 , lithium diisopropylamide claim 1 , and a tertiary organic amine.4. (canceled)6. The method of claim 5 , wherein the N-demethylation of step (i) is conducted in the presence of 1-chloroethyl chloroformate.7. The method of claim 5 , wherein the O-demethylation of step (iii) is conducted in the presence of hydrobromic acid.8. The method of claim 5 , wherein the base used in step (ii) is chosen from sodium carbonate claim 5 , cesium carbonate claim 5 , potassium carbonate claim 5 , sodium bicarbonate claim 5 , potassium bicarbonate claim 5 , sodium hydroxide claim 5 , potassium hydroxide claim 5 , potassium tert-butoxide claim 5 , sodium hydride claim 5 , n-butyllithium claim 5 , lithium diisopropylamide claim 5 , and a tertiary organic amine.10. (canceled)12. The method of claim 11 , wherein the base used in step (i) is chosen from potassium carbonate claim 11 , sodium hydride claim 11 , sodium methoxide claim 11 , and potassium t-butoxide.13. The method of claim 12 , wherein the base is potassium t-butoxide.14. The method of claim 13 , wherein the temperature used in step (i) is in the range of −3° C. to −1° C. inclusive.15. The method of claim 11 , wherein the base used in step (ii) is chosen from sodium carbonate claim 11 , cesium carbonate claim 11 , potassium carbonate claim 11 , sodium bicarbonate claim 11 , potassium bicarbonate claim 11 , sodium hydroxide claim 11 , potassium hydroxide claim 11 , potassium tert- ...

OPIOID AGONISTS AND USES THEREOF

Provided are compounds, including those of Formula I; and pharmaceutically acceptable salts and solvates thereof. The compounds described herein relate to and/or have application(s) in (among others) the fields of drug discovery, pharmacotherapy, physiology, organic chemistry and polymer chemistry. 2. The compound of claim 1 , wherein Ris hydrogen.3. The compound of any one of the preceding claims claim 1 , wherein Ris alkyl.4. The compound of any one of the preceding claims claim 1 , wherein Ris cyclopropylmethyl.5. The compound of any one of the preceding claims claim 1 , wherein G is O and represents a double bond.6. The compound of any one of the preceding claims claim 1 , wherein Ris hydrogen.7. The compound of any one of the preceding claims claim 1 , wherein Ris selected from optionally substituted alkyl claim 1 , optionally substituted amino claim 1 , and -X-POLY.8. The compound of any one of the preceding claims claim 1 , wherein Ris optionally substituted amino.9. The compound of any one of the preceding claims claim 1 , wherein Ris amino substituted with an optionally substituted aryl or optionally substituted alkyl.10. The compound of any one of the preceding claims claim 1 , wherein Ris amino substituted with an optionally substituted phenyl.12. The compound of claim 11 , wherein q is 1.13. The compound of any one or claim 11 , wherein X is —NH—.14. The compound of any one of or claim 11 , wherein X is —O—.15. The compound of any one of to claim 11 , wherein POLY is a poly(alkylene oxide) oligomer.16. The compound of any one of to claim 11 , wherein POLY is a poly(ethylene oxide) oligomer.17. The compound of any one of to claim 11 , wherein POLY is capped with an optionally substituted alkyl.18. The compound of any one of to claim 11 , wherein POLY is capped with a methyl claim 11 , trifluoromethyl claim 11 , or methyl substituted with a carboxy group.20. The compound of claim 19 , wherein X is —O—.21. The compound of claim 19 , wherein X is —NH—.22. ...

CHROMANE, ISOCHROMANE AND DIHYDROISOBENZOFURAN DERIVATIVES AS mGluR2-NEGATIVE ALLOSTERIC MODULATORS, COMPOSITIONS, AND THEIR USE

The present invention provides certain substituted chromane, isochromane, and dihydroisobenzofuran compounds of formula (I): 3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein{'sup': '2', 'sub': 3', '3', '2', '2', '2', '3', '3', '2', '2', '2', '2', '2', '3', '2', '2', '2', '2', '3', '2', '3', '2', '2', '2', '3', '2', '3', '2', '3, 'Ris selected from H, cyclopropyl, —CH, —CH(CH), —CH—OH, —CH—OCH, —CF, —CHCHF, —CHCHF, —CHCF, —CH—O—CHF, —CH—O—CHF, —CH(CH)—O—CHF, —CH(CH)—O—CHF, —CH—NH—CHCF, and —CH—N(CH)—CHCF;'}{'sup': '2A', 'Ris selected from H and methyl;'}{'sup': '3', 'Ris selected from H and methyl; and'}{'sup': '3A', 'Ris selected from H and methyl.'}4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein{'sup': 2', '2A, 'Rand Rare both methyl; and'}{'sup': 3', '3A, 'Rand Rare both H.'}8. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein:ring B is a moiety selected from the group consisting of phenyl, cyclopentyl, cyclohexyl, pyridinyl, pyrimidinyl, pyrazolyl, thienyl, thiazolyl, thiadiazolyl, isoxazolyl, oxadiazolyl and oxazolyl;n is 0, 1, 2, or 3, provided that the value of n does not exceed the maximum number of substitutable hydrogen atoms on ring B; and{'sup': '1', 'sub': 1', '6', '1', '6', '1', '6', '1', '6', '2', '1', '6', '1', '6', '2', '1', '6, 'each R(when present) is independently selected from the group consisting of halogen, —CN, —OH, —(C-C) alkyl, —O—(C-C) alkyl, —(C-C) haloalkyl, —O—(C-C) haloalkyl, cyclopropyl, cyclobutyl, —NH, —NH(C-C)alkyl, —N(C-Calkyl), —C(O)O(C-C) alkyl, and phenyl.'}9. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein:ring B is a moiety selected from the group consisting of: phenyl, pyrazolyl, pyridinyl, thienyl, isoxazolyl, oxadiazolyl and oxazolyl;n is 0, 1, or 2; and{'sup': '1', 'sub': 3', '2, 'each R(when present) is independently selected from the group consisting of ...

NITROGEN-CONTAINING HETEROCYCLIC COMPOUNDS AND METHODS OF MAKING THE SAME

The present invention relates to 7-membered nitrogen-containing heterocyclic compounds and methods of making the same. Using a novel aza-[4+3] cycloaddition reaction, the 7-membered heterocyclic compounds are synthesized by reacting a first reactant and a second reactant. Exemplary first reactants and second reactants include α-halohydroxamates and dienes, respectively. 2. A [4+3] cycloaddition reaction product of{'sup': 1', '2', '3', '1', '2', '1', '2', '3', '10', '10, 'a first reactant represented by general formula RRXC—CO—NHYR, wherein Rand Rare the same or different and independently selected from hydrogen, halide, a substituted or un-substituted alkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle, amino, amido, alkoxy, acyloxy, thio, or silyl, or Rand Rin combination form a cycloalkyl or a heterocycle; Ris a substituted or unsubstituted alkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle, sulfinyl, sulfonyl, or silyl; X is a leaving group; and Y is O, S, SO, or NR, wherein Ris a hydrogen, a substituted or unsubstituted alkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle, sulfinyl, sulfonyl, or silyl; and'}a second reactant having a diene moiety.3. A method of making a 7-membered nitrogen-containing heterocyclic compound via a [4+3] cycloaddition reaction , the method comprising:{'sup': 1', '2', '3', '1', '2', '1', '2', '3', '10', '10, 'combining a first reactant, a second reactant, and an activator to form a reaction mixture, the first reactant represented by general formula RRXC—CO—NHYR, wherein Rand Rare the same or different and are independently selected from hydrogen, halide, a substituted or un-substituted alkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle, amino, amido, alkoxy, acyloxy, thio, or silyl, or Rand Rin combination form a cycloalkyl or a heterocycle; Ris a substituted or unsubstituted alkyl, acyl, aryl, alkaryl, alkenyl ...

SUBSTITUTED SPIROPIPERIDINYL COMPOUNDS USEFUL AS GPR120 AGONISTS

The present invention relates to a compound represented by formula (I): and pharmaceutically acceptable salts thereof are disclosed as useful for treating or preventing diabetes, hyperlipidemia, obesity, inflammation related disorders, and related diseases and conditions. The compounds are useful as agonists of the G-protein coupled receptor GPR120. Pharmaceutical compositions and methods of treatment are also included. 2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein ring A is phenyl.3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein ring B is a (C)cycloalkyl claim 2 , wherein cycloalkyl forms a spiro ring system with the adjoining piperidinyl ring.4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein ring B is cyclohexenyl claim 2 , wherein cyclohexenyl forms a spiro ring system with the adjoining piperidinyl ring.5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein ring B is a 5- or 6-membered heterocycloalkyl containing 1 O ring atom claim 1 , wherein heterocycloalkyl forms a spiro ring system with the adjoining piperidinyl ring.6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein ring A is pyridinyl or pyrimidinyl.7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof claim 6 , wherein ring B is a (C)cycloalkyl claim 6 , wherein cycloalkyl forms a spiro ring system with the adjoining piperidinyl ring.8. The compound of claim 6 , or a pharmaceutically acceptable salt thereof claim 6 , wherein ring B is cyclohexenyl claim 6 , wherein cyclohexenyl forms a spiro ring system with the adjoining piperidinyl ring.9. The compound of claim 6 , or a pharmaceutically acceptable salt thereof claim 6 , wherein ring B is a 5- or 6-membered heterocycloalkyl containing 1 O ring atom claim 6 , wherein heterocycloalkyl forms a spiro ring system with the ...

Phenoxyethyl Cyclic Amine Derivatives and Their Activity as EP4 Receptor Modulators

The present invention provides a compound of the Formula (I): wherein X, R, R, R, R, R, R, R, R, R, and Rare as defined herein, or a pharmaceutically acceptable salt thereof. 2. The compound or salt according to wherein R is methyl.3. The compound or salt according to wherein Ris F and Ris F.4. The compound or salt according to wherein Ris methyl and Ris methyl.5. The compound or salt according to wherein Ris F and Ris F.8. A method of treating osteoarthritis in a patient claim 1 , comprising administering to a patient in need of such treatment an effective amount of a compound claim 1 , or pharmaceutically acceptable salt thereof claim 1 , according to .9. A method of treating rheumatoid arthritis in a patient claim 1 , comprising administering to a patient in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof claim 1 , according to .10. A method of treating pain associated with osteoarthritis or rheumatoid arthritis in a patient claim 1 , comprising administering to a patient in need of such treatment an effective amount of a compound or a pharmaceutically acceptable salt thereof claim 1 , according to .11. (canceled)12. (canceled)13. (canceled)14. (canceled)15. A pharmaceutical composition claim 1 , comprising a compound or a pharmaceutically acceptable salt thereof according to with one or more pharmaceutically acceptable carriers claim 1 , diluents claim 1 , or excipients. The present invention relates to certain novel phenoxyethyl compounds, to pharmaceutical compositions comprising the compounds, to methods of using the compounds to treat physiological disorders, and to intermediates and processes useful in the synthesis of the compounds.The present invention is in the field of treatment of inflammatory conditions, such as arthritis, including osteoarthritis and rheumatoid arthritis, and further including pain associated with these conditions. Arthritis affects millions of patients in the United States alone ...

COMPOUNDS AND METHODS FOR TREATING CANCER, NEUROLOGICAL DISORDERS, ETHANOL WITHDRAWAL, ANXIETY, DEPRESSION, AND NEUROPATHIC PAIN

Provided herein, inter alia, are compounds and methods of treating diseases including cancer, neurological disease, alcohol withdrawal, depression and anxiety, and neuropathic pain. 153.-. (canceled)55. The compound of claim 54 , wherein Ris halogen.56. The compound of claim 54 , wherein{'sup': 2', '4', '4', '4', '4A', '4', '4', '4A', '4', '4', '4', '4A', '4', '4A', '4', '4A, 'sub': n2', 'n2', 'n2, 'Ris halogen, —CN, —C(O)R, —OR, —NRR, —C(O)OR, —C(O)NRR, —S(O)R, —S(O)OR, —S(O)NRR, —ONRR, —NHC(O)NHNRR, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.'}57. The compound of claim 54 , wherein Ris halogen claim 54 , —OR claim 54 , —NRR claim 54 , —C(O)OR claim 54 , substituted or unsubstituted alkyl claim 54 , substituted or unsubstituted cycloalkyl claim 54 , substituted or unsubstituted heterocycloalkyl claim 54 , substituted or unsubstituted aryl claim 54 , substituted or unsubstituted heteroaryl.58. The compound of claim 54 , wherein Ris halogen claim 54 , —OR claim 54 , —NRR claim 54 , substituted or unsubstituted alkyl claim 54 , substituted or unsubstituted heterocycloalkyl claim 54 , substituted or unsubstituted aryl claim 54 , substituted or unsubstituted heteroaryl.59. The compound of claim 54 , wherein{'sup': 1', '3', '3', '3A', '3', '3', '3', '3, 'sub': 1', '10, 'Ris Cl, F, Br, —OH, —OR, —NRR, R-substituted or unsubstituted C-Calkyl, R-substituted or unsubstituted heterocycloalkyl, R-substituted or unsubstituted aryl, R-substituted or unsubstituted heteroaryl,'}{'sup': '3A', 'Ris hydrogen;'}{'sup': 3', '3B', '3B', '3B', '3B', '3B', '3B, 'sub': 3', '2', '2', '3', '2', '2', '2', '2, 'Ris —CF, —CN, —OH, —NH, —CONH, —S(O)H, —S(O)NH, —NHC(O) NH, —NHC(O)H, —OCHF, R-substituted or unsubstituted alkyl, R-substituted or unsubstituted heteroalkyl, R-substituted or ...

METHODS AND COMPOSITIONS FOR TERPENOID SYNTHESIS

In one aspect, the disclosure relates to methods for preparation of terpene and terpene-like molecules. In a further aspect, the disclosure relates to the products of the disclosed methods, i.e., terpene and terpene-like molecules prepared using the disclosed methods. Intermediates for the synthesis of a wide variety of terpenoids are γ-allyl Knoevenagel adducts or quasi γ-allyl Knoevenagel adducts are disclosed. In various aspects, methods of preparing terpenoids through these intermediates are disclosed. The methods can comprise a-alkylation of an allylic electrophile followed by ring-closure metathesis to a polycyclic terpenoid structure. In a further aspect, the disclosure pertains to terpenoid frameworks, and compounds prepared via disclosed oxidation and substitution reactions on the disclosed terpenoid frameworks. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure. 13. The method of claim 8 , wherein X is acetoxy claim 8 , t-butyloxycarbonoxy claim 8 , or Br.15. The method of claim 1 , further comprising:reacting the γ-allyl Knoevenagel adduct or a quasi γ-allyl Knoevenagel adduct with an allyl comprising electrophile to form an α,γ-diallyl Knoevenagel adduct or quasi α,γ-diallyl Knoevenagel adduct; andcatalyzing a ring-closure metathesis of the α,γ-diallyl Knoevenagel adduct or quasi α,γ-diallyl Knoevenagel adduct thereby forming a compound with a terpenoid framework. This Application claims the benefit of U.S. Provisional Application No. 62/394,852, filed on Sep. 15, 2016, which is incorporated herein by reference in its entirety.Structurally complex terpenoid natural products have been recognized as important therapeutic agents. Many terpenoid natural products contain a polycyclic core bearing a medium-sized 7- to 9-membered ring; examples of which are illustrated in . For example, taxol and ingenol are clinically used for the treatment of cancer and ...

METHOD OF USING SUBSTITUTED 2-AZA-BICYCLO[2.2.2]OCTANE-3-CARBOXYLIC ACID (BENZYL-CYANO-METHYL)-AMIDES INHIBITORS OF CATHEPSIN C

This invention relates to 2-Aza-bicyclo[2.2.2]octane-3-carboxylic acid (benzyl-cyano-methyl)-amides of formula 1 118-. (canceled)20. The method according to claim 19 , wherein Ris Rand Ris independently selected from among H claim 19 , C-alkyl- claim 19 , F— and HO—.21. The method according to claim 19 , wherein Ris Rand Ris H claim 19 , F claim 19 , Cl claim 19 , phenyl-HC—O— claim 19 , HO— claim 19 , C-alkyl- claim 19 , C-haloalkyl- claim 19 , C-cycloalkyl- claim 19 , C-alkyl-O— and C-haloalkyl-O—.22. The method according to claim 19 , wherein Ris Rand Ris H or F.23. The method according to claim 19 , wherein A is Aand Ais a bond or independently selected from{'sup': 5', '5', '5', '5', '5', '5', '5', '5', '5.a', '5.a, 'sub': 2', '2', '2', '1-4, 'among —O—, —C(O)N(R)—, —N(R)C(O)—, —S(O)N(R)—, —N(R)S(O)—, —C(O)O—, —OC(O)—, —C(O)—, —S(O)—, —(R)(O)S═N—, —(RN═)(O)S— and —N═(O)(R)S—, and Ris Rand Ris independently selected from among H, C-alkyl- and NC—.'}24. The method according to claim 19 , wherein Ris Rand{'sup': 2.1', '2.1.a', '2.1.a', '2.1.1', '2.1.1', '2.1.1', '2.1.1, 'sub': 1-4', '1-4', '3-6', '1-4', '1-4', '1-4', '1-4', '3-6', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4, 'claim-text': [{'sup': 2.1.1', '2.1.1.a', '2.1.1.a, 'claim-text': [{'sup': '2.1.1.1', 'aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R;'}, {'sub': 5-10', '2, 'sup': 2.1.1.1', '2.1.1.2, 'C-heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(O), S(O), O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R; and'}, {'sub': 5-10', '2, 'sup': 2.1.1.1', '2.1.1.2, 'C-heterocyclyl-, containing one, two, three or four heteroatoms selected ...

Spirocentric Compounds and Polymers Thereof

The present invention is directed to novel functionalized spirocentric compounds and polymers thereof that produce hyper-rigid cross-linked membranes. 19. The compound according to claim 18 , wherein:{'sub': '3', 'Z is selected from —N, —C≡CH, and C≡C—R′;'}{'sub': 2', '2, 'claim-text': [{'sub': '1-6', 'Y is independently absent or selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —NH—(C═O)—; ═NO—Calkyl-; and —(C═O)-phenyl-;'}, {'sub': 3', '2', '3', '6', '6', '2', '6', '3', '6', '2, 'Z is independently selected from —N, —C≡CH, C≡C—R′, —C≡N, —(C═O)—H, —SH, —CH═CH, halide, —SOR, —B(OR), Sn(R), and Zn(R);'}, {'sub': 2', '6', '6', '2', '6, 'R′ is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —COR, —(C═O)—N(R), and —(C═O)—R; and'}, {'sub': 3', '4, 'R″ is selected from Rand R.'}], 'R′ is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —COR″, —(C═O)—N(R″), and —(C═O)—R″; and'}18. A compound according to Formula III: This application claims the benefit of priority to U.S. Provisional Patent Application No. 62/753,470, filed 31 Oct. 2018, and titled “FUNCTIONALIZED MEMBRANES AND METHODS OF PRODUCTION THEREOF,” and also claims the benefit of priority to U.S. Provisional Patent Application No. 62/640,253, filed 8 Mar. 2018, and titled “SPIROCENTRIC COMPOUNDS AND POLYMERS THEREOF,” both of which are incorporated herein by reference in their entireties.The present invention relates to novel functionalized spirocentric compounds and polymers thereof and their use for making hyper-rigid cross-linked membranes.Microporous hyper rigid polymeric membranes have emerged as energy efficient molecular separation platforms ...

BENZOMORPHAN ANALOGS AND THE USE THEREOF

In one aspect, the invention provides compounds of Formula (I) or (II): (I) or (II) and pharmaceutically acceptable salts and solvates thereof, wherein R, R, R, R, R, Z and G are defined as set forth in the disclosure. The invention also provides compounds of Formulae A and B and pharmaceutically acceptable salts and solvates thereof. Other aspects of the invention include the use of compounds of Formulae I, II, A, and B, and pharmaceutically acceptable salts and solvates thereof for the treatment of disorders responsive to modulation of one or more opioid receptors. In certain embodiments, the Compounds of the Invention are useful for treating pain. 4. (canceled)5. The compound of claim 2 , wherein Z is optionally-substituted —(CH)— claim 2 , and m is 1 claim 2 , 2 claim 2 , 3 claim 2 , or 4.69-. (canceled)10. The compound of claim 2 , wherein G is —N(R)C(O)N(R)— claim 2 , and each of Rindependently is hydrogen or —(C-C)alkyl.1113-. (canceled)14. The compound of claim 10 , wherein Ris selected from the group consisting of -(6- to 14-membered)aryl claim 10 , —(C-C)alkyl-(6- to 14-membered)aryl claim 10 , and —S(O)-(6- to 14-membered)aryl; each of which is optionally substituted with a substituent selected from the group consisting of —(C-C)alkyl claim 10 , halo claim 10 , —COOR claim 10 , —NHC(O)(C-C)alkyl claim 10 , —NH claim 10 , -(6- to 14-membered)aryl claim 10 , aryloxy claim 10 , carboxamido claim 10 , and —SONH.15. The compound of claim 14 , wherein Ris selected from the group consisting of phenyl claim 14 , —(C-C)alkyl-phenyl claim 14 , and —S(O)-phenyl claim 14 , each of which is optionally substituted with a substituent selected from the group consisting of halo claim 14 , —COOR claim 14 , phenyl claim 14 , and -OPh claim 14 , and wherein Ris hydrogen or —(C-C)alkyl.16. The compound of claim 2 , wherein G is —O—.17. (canceled)18. The compound of claim 16 , wherein Ris selected from the group consisting of hydrogen claim 16 , —(C-C)alkyl claim 16 , -(6- to ...

Condensed cyclic compound and organic light-emitting device comprising the same

A condensed cyclic compound represented by Formula 1 and an organic light-emitting device including the condensed cyclic compound are provided;

6-SUBSTITUTED AND 7-SUBSTITUTED MORPHINAN ANALOGS AND THE USE THEREOF

The application is directed to compounds of Formula I or II: and pharmaceutically acceptable salts and solvates thereof, wherein R′, R″, R′″ R, R, R, R, R, and Rare defined as set forth in the specification. The invention is also directed to use of compounds of Formula I or II and the pharmaceutically acceptable salts and solvates thereof to treat disorders responsive to the modulation of one or more opioid receptors. Certain compounds of the invention are especially useful for treating pain. 4. (canceled)725-. (canceled)27. (canceled)28. (canceled)29. The compound of claim 2 , wherein Ris —Z-G-R.30. The compound of claim 29 , wherein Ris selected from the group consisting of —(C-C)alkyl unsubstituted or substituted with OH; -(6- to 14-membered)aryl; ((6- to 14-membered)aryl)-(C-C)alkyl-; -(3- to 12-membered)cycloalkyl; ((3- to 12-membered)cycloalkyl)-(C-C)alkyl-; —(C-C)alkoxy; -(3- to 12-membered)heterocycle; ((3- to 12-membered)heterocycle)-(C-C)alkyl; —COOR; —(C-C)alkyl-COOR; -(6-14-membered)aryl substituted with —NH—C(═NH)—NRR; ((6-14-membered)aryl)-(C-C)alkyl-substituted with NH—C(═NH)—NRR; —NRR; —(C-C)alkyl-NRR; and —(C-C)alkyl-NH—C(═NH)—NRR;{'sup': '7', 'wherein Ris hydrogen;'}3162-. (canceled)63. The compound of claim 30 , wherein at least one of Rand Ris hydrogen or —(C-C)alkyl.6466-. (canceled)67. The compound of claim 29 , wherein Gis a bond claim 29 , —C(═O)— claim 29 , —O— claim 29 , —O—C(═O)— claim 29 , —NR claim 29 , —NH—C(═O) claim 29 , or —NH—C(═NH); wherein Ris hydrogen.6869-. (canceled)70. The compound of claim 29 , wherein Zis (CH) claim 29 , wherein m is 0 or 1.72. (canceled)73. The compound of claim 2 , wherein Ris —Z-G-R.74. The compound of claim 73 , wherein Ris —(C-C)alkyl unsubstituted or substituted with OH; —(C-C)alkoxy; -(6- to 14-membered)aryl; -(6- to 14-membered)aryl substituted with —NH—C(═NH)—NRR; ((6- to 14-membered)aryl)-(C-C)alkyl-substituted with —NH—C(═NH)—NRR; —NRR; —(C-C)alkyl-NRR; or —(C-C)alkyl-NH—C(═NH)—NRR.7596-. ( ...

MORPHAN AND MORPHINAN ANALOGUES, AND METHODS OF USE

The present application relates to analogues of morphan and morphinan, compositions thereof, and methods for treating a disease or condition comprising administering an effective amount of the compounds or compositions to a subject in need thereof. 15-. (canceled)7. The compound of claim 6 , wherein Ris C-Calkenyl or cycloalkyl.8. The compound of claim 6 , wherein Rand Rare each methyl.9. The compound of claim 6 , wherein is a single bond claim 6 , and Ris H.11. The compound of claim 10 , wherein Ris C-Calkenyl or cycloalkyl.12. The compound of claim 10 , wherein Rand R claim 10 , together with the carbon atoms to which they are attached claim 10 , form a 6-membered unsubstituted carbocyclic ring or a 6-membered carbocyclic ring substituted with a hydroxyl or a ketone.13. The compound of claim 10 , wherein Rand R claim 10 , taken together with the carbon atom to which they are attach to claim 10 , form a C═O group.14. The compound of claim 10 , wherein Ris substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N claim 10 , O and S.16. The compound of claim 15 , wherein Ris cyclopropyl.17. The compound of claim 15 , wherein X is H or hydroxyl.18. The compound of claim 15 , wherein Y and Z are each claim 15 , independently claim 15 , H or hydroxyl claim 15 , or alternatively claim 15 , Y and Z claim 15 , together with the carbon atom to which they are attached claim 15 , form C═O.19. The compound of claim 15 , wherein Ris —C(O)NH.21. The compound of claim 6 , wherein the compound is a μ opioid receptor agonist having an Emax of 5% to 45% in a GTPγS binding assay.22. The compound of claim 21 , wherein the Emax is 15% to 35% in a GTPγS binding assay.23. The compound of claim 21 , wherein the agonist has a low risk of opioid dependence claim 21 , opioid addiction claim 21 , and/or symptoms of opioid withdrawal.24. The compound of claim 6 , having a maximal dopamine efflux in the nucleus accumbens of 125% to 300% over ...

Amido Compounds And Their Use As Pharmaceuticals

The present invention relates to inhibitors of 11-β hydroxyl steroid dehydrogenase type 1, antagonists of the mineralocorticoid receptor (MR), and pharmaceutical compositions thereof. The compounds of the invention can be useful in the treatment of various diseases associated with expression or activity of 11-β hydroxyl steroid dehydrogenase type 1 and/or diseases associated with aldosterone excess.

RING-CONTRACTED MORPHINANS AND THE USE THEREOF

The application is directed to compounds of Formula (I) or (IA) and pharmaceutically acceptable salts and solvates thereof, wherein RR, and G are defined as set forth in the specification. The invention is also directed to use of compounds of Formula (I) or(IA), and the pharmaceutically acceptable salts and solvates thereof, to treat disorders responsive to the modulation of one or more opioid receptors, or as synthetic intermediates. Certain compounds of the present invention are especially useful for treating pain. 4. (canceled)611-. (canceled)12. The compound of claim 2 , or a pharmaceutically acceptable salt or solvate thereof claim 2 , wherein Ris hydrogen claim 2 , hydroxy claim 2 , halo claim 2 , cyano claim 2 , carboxy claim 2 , or aminocarbonyl; or alkyl claim 2 , alkenyl claim 2 , alkynyl claim 2 , alkoxy claim 2 , alkenyloxy claim 2 , or alkynyloxy claim 2 , any of which is optionally substituted with 1 claim 2 , 2 claim 2 , or 3 substituents claim 2 , each independently selected from the group consisting of hydroxy claim 2 , halo claim 2 , haloalkyl claim 2 , amino claim 2 , alkylamino claim 2 , dialkylamino claim 2 , carboxy claim 2 , alkoxy claim 2 , alkoxycarbonyl claim 2 , aryl claim 2 , heteroaryl claim 2 , heterocyclo claim 2 , cycloalkyl claim 2 , and cycloalkenyl claim 2 , wherein said aryl claim 2 , heteroaryl claim 2 , heterocyclo claim 2 , cycloalkyl claim 2 , and cycloalkenyl are optionally substituted with 1 claim 2 , 2 claim 2 , or 3 independently selected Rgroups.13. The compound of claim 12 , or a pharmaceutically acceptable salt or solvate thereof claim 12 , wherein Ris hydroxy or unsubstituted Calkoxy.1419-. (canceled)20. The compound of claim 2 , or a pharmaceutically acceptable salt or solvate thereof claim 2 , wherein Ris cyclopropyl(C)alkyl claim 2 , cyclobutyl(C)alkyl claim 2 , cyclopentyl(C)alkyl claim 2 , or cyclohexyl(C)alkyl claim 2 , optionally substituted with 1 claim 2 , 2 claim 2 , or 3 substituents claim 2 , each ...

Morphinan Derivatives for the Treatment of Drug Overdose

The instant application relates to morphinan derivatives of Formula I with sustained effectiveness in treating drug toxicity and overdose: 2. The method according to claim 1 , wherein said first opioid receptor antagonist is naloxone.3. The method according to any one of claim 1 , wherein said drug toxicity or overdose is resulting from opioid administration to a non-dependent patient.4. The method according to claim 3 , wherein said subject is an opioid experienced non-dependent opioid user.5. The method according to claim 2 , wherein said administration of compound of Formula I is preceded by said naloxone administration.6. The method according to claim 5 , wherein said naloxone administration reduces symptoms of overdose or toxicity prior to administration of compounds of Formula I.7. The method according to any one of claim 1 , wherein said compound of Formula I is administered in a daily dose of about 3 to about 20 mg/day.8. The method according to claim 7 , wherein said daily dose is about 10 mg/day.9. The method according to claim 1 , wherein administration of a compound of Formula I reduces symptoms of opioid toxicity or overdose over a period of at least about 15 to about 30 minutes.10. The method according to claim 9 , wherein symptoms of opioid toxicity or overdose are reduced for a period of at least one hour.11. The method according to claim 9 , wherein symptoms of opioid toxicity or overdose are reduced for a period of at least two hours.12. The method according to claim 9 , wherein symptoms of opioid toxicity or overdose are reduced for a period of at least three hours.13. The method according to claim 9 , wherein symptoms of opioid toxicity or overdose are reduced for a period of at least four hours.14. The method according to claim 9 , wherein symptoms of opioid toxicity or overdose are reduced for a period of at least eight hours.15. The method according to any one of claim 9 , wherein said administration comprises about 3 mg to about 20 mg of a ...

Crystalline Forms Of Mesaconine And Preparation Methods Therefor

The present invention relates to crystalline forms of mesaconine. Specifically, the present invention relates to crystalline form A, crystalline form B and crystalline form C of mesaconine and preparation methods thereof. In the method, the mesaconine is crystallized in solvent, and then the crude crystal is dried to obtain target crystalline form. The crystalline forms of mesaconine according to the present invention have good solubility, good stability, low hygroscopicity, long-term storage capability and good reproducibility, and have a good prospect to be developed as pharmaceuticals. 1. Crystalline form A of mesaconine , wherein , the crystalline form A of mesaconine exhibits characteristic peaks at 2θ of 8.3°±0.2° , 10.6°±0.2° , 13.3°±0.2° , 13.7°±0.2° and 19.0°±0.2° in powder X-ray diffraction spectrum using Cu-Kα radiation.2. The crystalline form A of mesaconine according to claim 1 , wherein claim 1 , the crystalline form A of mesaconine also exhibits characteristic peaks at 2θ of 11.6°±0.2° claim 1 , 19.8°±0.2° claim 1 , 24.2°±0.2° and 26.9°±0.2° in powder X-ray diffraction spectrum using Cu-Kα radiation.3. A method for preparing the crystalline form A of mesaconine according to claim 1 , wherein claim 1 , the method comprises steps of:(1) adding mesaconine into a solvent, then heating the obtained solution to 50˜90° C. to dissolve the mesaconine so as to obtain a mesaconine solution;(2) cooling the mesaconine solution to −10˜30° C., stirring the solution to precipitate crystal, and then performing filtration;(3) drying the solid obtained by filtration in the step (2) at vacuum to obtain the crystalline form A of mesaconine.4. The method according to claim 3 , wherein claim 3 , the solvent is selected from a group consisting of water claim 3 , methanol claim 3 , ethanol claim 3 , isopropanol claim 3 , acetone and acetonitrile and combinations thereof.512-. (canceled)13. A pharmaceutical composition comprising the crystalline form A of mesaconine according ...

OPIOID AGONISTS AND USES THEREOF

Provided are compounds, including those of Formula I; and pharmaceutically acceptable salts and solvates thereof. The compounds described herein relate to and/or have application(s) in (among others) the fields of drug discovery, pharmacotherapy, physiology, organic chemistry and polymer chemistry. 2. The compound of claim 1 , wherein Ris hydrogen.3. The compound of any one of the preceding claims claim 1 , wherein Ris alkyl.4. The compound of any one of the preceding claims claim 1 , wherein Ris cyclopropylmethyl.5. The compound of any one of the preceding claims claim 1 , wherein G is O and represents a double bond.6. The compound of any one of the preceding claims claim 1 , wherein Ris hydrogen.7. The compound of any one of the preceding claims claim 1 , wherein Ris selected from optionally substituted alkyl claim 1 , optionally substituted amino claim 1 , and —X-POLY.8. The compound of any one of the preceding claims claim 1 , wherein Ris optionally substituted amino.9. The compound of any one of the preceding claims claim 1 , wherein Ris amino substituted with an optionally substituted aryl or optionally substituted alkyl.10. The compound of any one of the preceding claims claim 1 , wherein Ris amino substituted with an optionally substituted phenyl.12. The compound of claim 11 , wherein q is 1.13. The compound of any one or claim 11 , wherein X is —NH—.14. The compound of any one of or claim 11 , wherein X is —O—.15. The compound of any one of to claim 11 , wherein POLY is a poly(alkylene oxide) oligomer.16. The compound of any one of to claim 11 , wherein POLY is a poly(ethylene oxide) oligomer.17. The compound of any one of to claim 11 , wherein POLY is capped with an optionally substituted alkyl.18. The compound of any one of to claim 11 , wherein POLY is capped with a methyl claim 11 , trifluoromethyl claim 11 , or methyl substituted with a carboxy group.20. The compound of claim 19 , wherein X is —O—.21. The compound of claim 19 , wherein X is —NH—.22. ...

Novel Spiro and Cyclic Bis-Benzylidene Proteasome Inhibitor for the Treatment of Cancer, Diabetes and Neurological Disorders

Described herein are spiro and cyclic bis-benzylidine proteasome inhibitors, which inhibit the proteasome function through either ubiquitin receptor ADRM1/RPN13 or proteasome DUB enzymes (USP14, UCH37 and RPN11), and which can be used for the treatment of cancers/diabetes/neurological disorders. 2. A compound according to which binds to proteasomal proteins as either DUB inhibitor or proteasome receptor inhibitor.3. A method of inhibiting proteasomes in a mammal by ad ministering to the mammal an effective amount of the compound of .4. A method of treating or a disease in a mammal by administering to the mammal a therapeutically effective dose of the compound of .5. The method of wherein the mammal is a human claim 4 , or a dog claim 4 , or a cat.6. The method of wherein the disease is a type of cancer or diabetes or neurological disorders.7. The method of wherein the compound of is administered alone or in combination with at least one other therapeutic agent or radiation. Ubiquitin-Proteasome System (UPS) play a vital role in cellular homeostasis, cell cycle progression and signaling pathways that are altered in many diseases. Modulating UPS function with small molecules that directly bind to the proteasomal proteins can be useful to treat wide variety of diseases specifically cancers, diabetes and neurological disorders. Targeting the aberrant metabolism of cancer cells is an emerging approach for cancer therapy. Indeed, despite early skepticism that inhibiting protein degradation with a proteasome inhibitor would provide a sufficient therapeutic index for cancer therapy, over the last decade three proteasome inhibitors that target the catalytic function of the 20S proteasome were approved by FDA to treat multiple myeloma and mantle cell lymphoma. However, their limited efficacy against solid tumors, toxicities and the emergence of resistant multiple myeloma has driven search for alternative proteasome inhibitors with distinct and complementary mechanisms of ...

(--)-Huperzine A Processes and Related Compositions and Methods of Treatment

The invention provides (1) processes for making substantially-pure (−) huperzine A and substantially-pure (−) huperzine A derivatives; (2) compositions useful in making substantially-pure (−) huperzine A and substantially-pure (−) huperzine A derivatives; and (3) methods of treating or preventing neurological disorders using substantially-pure (−) huperzine A and substantially-pure (−) huperzine A derivatives. 13-. (canceled)47-. (canceled)9. The process of claim 8 , wherein the addition alkylation product is reacted in a solvent selected from the group consisting of TILT or toluene claim 8 , the palladium-catalyzed intramolecular enolate heteroarylation base is sodium tert-butoxide claim 8 , the Wittig olefination reaction base is selected from the group consisting of n-butyllithium claim 8 , sodium bis(trimethylsilyl)amide claim 8 , lithium bis(trimethylsilyl)amide claim 8 , potassium bis(trimethylsilyl)amide or lithium diisopropylamide claim 8 , and the Wittig olefination reaction organic solvent is selected from the group consisting of THF claim 8 , diethylether or 1 claim 8 ,4-dioxane.10. (canceled)12. The process of claim 11 , wherein:(a) the addition alkylation product is reacted with lithium bis(trimethylsilyl) amide (LHMDS) or lithium diisopropyl amide (LDA) in THF or toluene;(b) the palladium-catalyzed intramolecular enolate heteroarylation base is sodium tert-butoxide;(c) the Wittig olefination reaction base is selected from the group consisting of n-butyllithium, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide and lithium diisopropylamide; and the Wittig olefination reaction organic solvent is selected from the group consisting of THF, diethylether or 1,4-dioxane;(d) the oxidative disilylation Bronsted acid is selected from the group consisting of TFA, MSA, FMSA, or tetrafluoroboric acid;(e) the oxidative disilylation inert solvent is DCM;(f) the cyanoalcohol dehydration organic solvent is toluene;(g) ...

DEXTRORPHAN PRODRUGS AND PROCESSES FOR MAKING AND USING THEM

The presently described technology provides compositions of one or more of oxoacids, polyethylene glycols, and/or vitamin compounds chemically conjugated to dextrorphan, (+)-17-methylmorphinan-3-ol), to form novel prodrugs and compositions of dextrorphan. 131-. (canceled)33. The compound of claim 32 , wherein Land Yare absent claim 32 , Gis at least one oxoacid claim 32 , and m is 1-3.34. The compound of claim 32 , wherein Land Yare present claim 32 , Gis at least one oxoacid claim 32 , and m is 1-3.35. The compound of claim 32 , wherein Gis at least one oxoacid selected from the group consisting of aliphatic carboxylic acid claim 32 , aryl carboxylic acid claim 32 , dicarboxylic acid claim 32 , polycarboxylic acid claim 32 , standard amino acids claim 32 , non-standard amino acids claim 32 , and synthetic amino acids claim 32 , and combinations thereof.36. The compound of wherein Gis a combination of at least two oxoacids claim 35 , wherein at least one of the at least two oxoacids is selected from the group consisting of aliphatic carboxylic acid claim 35 , aryl carboxylic acid claim 35 , dicarboxylic acid claim 35 , and polycarboxylic acid claim 35 , and combinations thereof claim 35 , and at least one of the at least two oxoacids is selected from standard amino acids claim 35 , non-standard amino acids claim 35 , synthetic amino acids claim 35 , and combinations thereof.37. The compound of claim 36 , wherein the at least one of the at least two oxoacids is valine.40. The compound of claim 39 , wherein where Land Yare absent claim 39 , M is —(CRR) claim 39 , Gis at least one oxoacid claim 39 , and m is 1-3.41. The compound of claim 39 , wherein the at least one oxoacid is acetic acid.44. The compound of claim 43 , wherein at least one of Gand Gis at least one oxoacid.45. The compound of claim 44 , wherein Gand Gare each acetic acid.48. A composition wherein the composition comprises the compound of or a pharmaceutically acceptable salt of the compound.49. A ...

INDUSTRIAL PROCESS OF MONO-ALKYLATING PIPERIDINE NITROGEN IN PIPERIDINE DERIVATIVE WITH DEUTERATED-LOWER-ALKYL

The present invention relates to a method of mono-alkylating a piperidine nitrogen in a piperidine derivative with a deuterated lower-alkyl, which comprises protecting the piperidine nitrogen with an aralkyl protective group, lower-alkylating the piperidine nitrogen with a deuterated-lower-alkylating agent under neutral or basic condition, and then deprotecting the aralkyl protective group. 1. A method of mono-alkylating a piperidine nitrogen in a piperidine derivative with a deuterated lower-alkyl by protecting the piperidine nitrogen with an aralkyl protective group , lower-alkylating the piperidine nitrogen with a deuterated lower-alkyl agent under neutral or basic condition , and then deprotecting the aralkyl protective group.2. The method of claim 1 , wherein the piperidine derivative is a morphinan derivative.3. The method of claim 2 , wherein the morphinan derivative is N-desmethyl form of dextromethorphan (i.e. claim 2 , 3-methoxymorphinan).4. The method of claim 1 , wherein the mono-alkylation is mono-methylation or mono-ethylation claim 1 , and the deuterated-lower-alkylating agent is deuterated-methylating agent or deuterated-ethylating agent.5. The method of claim 1 , wherein the mono-alkylation is mono-methylation claim 1 , and the deuterated-lower-alkylating agent is [H]methyl methanesulfonate claim 1 , [H]methyl benzenesulfonate claim 1 , [H]methyl 4-methylbenzenesulfonate claim 1 , [H]methyl 2-nitrobenzenesulfonate claim 1 , [H]methyl 4-nitrobenzenesulfonate claim 1 , di-[H]methyl sulfate claim 1 , di-[H]methyl carbonate claim 1 , [H]methyl trifluoromethanesulfonate claim 1 , [H]methyl bromide claim 1 , or [H]methyl iodide.6. The method of claim 1 , wherein the aralkyl protective group is a benzyl-derivative protective group.7. The method of claim 6 , wherein the benzyl-derivative protective group is benzyl protective group.8. The method of claim 6 , wherein the deprotection is to deprotect the benzyl-derivative protective group by hydrogenation.9. ...

Solid pharmaceutical dispersions with enhanced bioavailability

Analgesiques tricycliques.

Chromogenic acridinone enzyme substrates

Chromogenic acridinone enzyme substrate compounds comprising 7-hydroxy-9H-acridin-2-one chromogens derivatized at the 7-hydroxy-position with an enzymatically-cleavable group and disubstituted at the 9-position with alkyl or aryl groups, which can be the same or different, preferably lower alkyl or phenyl, respectively, or together form a cyclohexa-2,5-diene-4-one residue or a 4-hydroxycycloxhexyl residue, and 7-hydroxy-1,3-dihalo-9,9-dimethyl-acridin-2-one intermediates useful for the preparation of the novel chromogenic acridinone enzyme substrate compounds and methods therefor. The enzymatically-cleavable group is a radical of a compound Y-OH comprising an enzyme-specific moiety which is capable of being cleaved by a specific enzyme wherein a deprotonated form of the chromogen is liberated having an absorbance maximum in basic solution which is substantially greater than the absorbance maximum of the chromogenic acridinone enzyme substrate compound to provide a distinct change in absorbance which can be accurately measured and correlated to the amount of enzyme present in a liquid test sample.

CD4 MIMIC COMPOUND WITH ANTI-HIV ACTIVITY

CD4 mimic compounds having improved efficacy for anti-HIV treatment and more improved pharmacokinetics are provided. The compounds are represented by formula (I): 3. The compound or a salt thereof according to claim 2 , wherein n is 4 to 23.4. An HIV infection inhibitor composition comprising a compound or a salt thereof according to .5. A method for treating or preventing HIV infection claim 4 , comprising administering a composition of to a patient in need thereof.6. The method according to claim 5 , wherein the HIV infection inhibitor which is administered in combination with an anti-HIV antibody.7. The method according to claim 6 , wherein the anti-HIV antibody is a neutralizing antibody specific to V3 loop on a surface of HIV-1.8. A method for treating or preventing HIV infection claim 1 , comprising administering a compound or a salt thereof of to a patient in need thereof.9. The method of claim 8 , further comprising administering an anti-HIV antibody with said compound or salt thereof.10. The method of claim 9 , wherein the anti-HIV antibody is a neutralizing antibody specific to V3 loop on a surface of HIV-1. The present invention relates to a novel CD4 mimic compound having an anti-HIV activity. More specifically, the present invention relates to a CD4 mimic compound having an improved pharmacokinetics.Human immunodeficiency virus (HIV) is known as a virus causing acquired immunodeficiency syndrome (AIDS). There are three main infection routes of HIV: sexual contact, infection through blood transfusion or blood preparations and mother-to-child infection, and there is no risk of aerial infection. To date, about 74.9 million people have been infected with HIV in the world. Of them, 32 million people have died from AIDS-related illnesses. Currently, chemotherapy with drugs for suppressing AIDS has been successful, but permanent cure of AIDS has not yet been attained.There are two types of HIV, HIV-1 and HIV-2. HIV-1 is further classified into subtypes A to K. ...

Dosage form containing two or more active pharmaceutical ingredients in different physical forms

Processo para fabricação de (9alfa, 13alfa, 14alfa),-1-(3-morfinan-17-il) alcanonas

METHOD OF OBTAINING 2- (FURILMETHIL) -6,7- BENZOMORPHANES

Method of preparing 2-tetra-hydrofurfuryl-6,7-benzomorphanes or salts thereof